Regulation of Cholesterol Biosynthesis and Catabolism

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					                              Regulation                                                                                  of                   Cholesterol                                                                          Biosynthesis

                                                                                                            and                                 Catabolism

            DAvID                        KRITCHEVSKY,                                PH.D.,*                        EZRA                 STAPLE,                     PH.D.t                 AND               MICHAEL           W.         WHITEHOUSE,                                   PH.D4

I           T     IS     flow              fairly                well              established                               that              the        liver which                  affect                 this            process.                           Today                     it        is      possible
            is a major                            site           of         cholesterol                             biosynthesis                                and to       assign              the          action                 of some                    of the               known                        stimu-
degradation.                                        These                    complex                         processes                           are,           of latory              and              inhibitory                          factors                    to         specific                    sites             in
course,     interrelated,                                                     but        for purposes                                      of          clarity the              biosynthetic                              scheme.
they    will he considered                                                            separately      here.

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                                                                                                                                                                           The             effects                 of       diet                were             among                       the             earliest
        Since                       the        demonstration                                              by             Bloch              and               Rit-
                                                                                      studied.            In the                                                                                                                intact,                fasting                       rat             there     is                    a
tenberg’         in     1942       that       a two-carbon              unit,      ace-
                                                                                      progressive            decrease                                                                                                                      in        biosynthetic                                    capacity,
tate,     could       provide          all the carbon           atoms         neces-
                                                                                      slightly         subnormal                                                                                                                     synthesis                               being                    observed
sary     for    cholesterol             biosynthesis,    most      steps       in
                                                                                      after     twenty-four                                                                                                                     hours,      a 50                          per cent                     decrease
the biosynthetic                pathway            have   been     elucidated.
                                                                                      after      forty-eight                                                                                                                  hours,                 and              a      67          per               cent             de-
Two       principal           features          of this      work        were       the
                                                                                      crease        in three                                                                                                               days.4                         However,                              liver                slices
demonstrations               of      the       seemingly          obligatory
                                                                                                                                                                     from           rats               fasted                 for          twenty-four                                  hours                     show             a
roles   of mevalonic                                                  acid    (#{244}-dihydroxy-3-methyl-
                                                                                                                                                                    more            marked                        drop              in cholesterogenesis.5                                           Star-
valeric    acid)2    and                                             squalene.3           The     generally                                                      ac-
                                                                                                                                                                     vation                is      actually                          not             necessary                           to           show                  this
cepted                         scheme                     of          cholesterol                              biosynthesis                               from
                                                                                                                                                                     effect,           for         even                 restriction                         of        caloric                   intake                   will
acetate                             is        outlined          in                              Figure          ,     1
                                                                                                                   although                               a
                                                                                                                                                                inhibit    hepatic                                      cholesterogenesis.56
number                              of        the      intermediate                                             compounds                                  have
                                                                                                                                                                    In a complete                                       diet,              the          presence                     of cholesterol
not               yet               been             fully                 identified.
                                                                                                                                                                     or     one             of         its         precursors                             will              impair                        liver             bio-
        Even                        when                 less          was             known                         of       the           details                  of
                                                                                                                                                                     genesis                of         this             sterol.                      Gould                   and                associates78
cholesterol                                   biosynthesis,                           a         number                         of         investi-
                                                                                                                                                                     demnonstrated             that                                      dietary           cholesterol          pro-
gators                        had            begun                     to          study                  some               of          the           factors
                                                                                                                                                                     foundly       affected      the                                   ability     of dogs         or rabbits      to
      From                    the          Wistar                Institute                      of        Anatomy                   amid             Biology,        convert           acetate                                        to       cholesterol.             Tomkins,
and               the           Department                             of         Biochemistry,                School               of      Medi-                    Sheppard                      and             Chaikoff9                         showed                    the            same                 situa-
cine,               University                      of     Pennsylvania,                              Philadelphia,                       Penn-                      tion    to            be      true             in the                 rat         (Tablei).                  In          rats            fed
                                                                                                                                                                     a 2 per               cent          cholesterol                             diet           for        two          weeks,                     hepa-
        *       Associate                     Member,                        the           \Vistar                   Institute of         Amiat-
omy                 and                  Biology,                    and            Assistant                            Professor of           Bio-
                                                                                                                                                                     tic       synthesis                        was             depressed                         75         to         90           per           cent.

chemistry,                                 School                of          Medicine,                         University of              Penn-                      In        rabbits                   fed            cholesterol                            over               longer                    periods,
sylvania;                            t     Assistant                          Professor                             of         Biochemistry,                         the         endogenous                              contribution                                  to         the           circulating
School                  of     Medicine,                        University                           of     Pennsylvania,                 Phila-                     cholesterol                          appeared                              to        be          only                 5         to           10         per
delphia,     Pennsylvania.             Demonstrater,           Department             of
                                                                                                                                                                     cent.”                      Feeding                            mevalonic                               acid,’2                       squalene,
Biochemistry,          University          Oxford,       Oxford,         England.
    Presented        at the Svmnposium               on    the      Role      of     Vita-                                                                           lathosterol                        (7-cholesterol)                                    or             7-dehydrocho-
mins     and     Other       Nutrients  in Lipid       Metabolism,             Tulane                                                                                lesterol’3’4                            to          rats              causes                     inhibition                              of         cho-
University                            School              of         Medicine,                        New           Orleans,                Louisiana,               lesterogenesis                           in        the           liver               (Table                   mm).               Lathos-
under                         the            sponsorship                    of            The               National                       Vitamin                   terol         has            been             shown                   to        be         converted                             to          choles-
Foundation,                                 Inc.,          October                    16,         1959.
                                                                                                                                                                     terol.’5                    Cholesterol                                and             7-dehydrocholesterol
      This                   work           was          supported                         in        part           by       grants                from          the
National                        Institutes                      of      Health                  (H-3299)                     and          the          John
                                                                                                                                                                                      to          be          interconvertible                             in         the            intestine.’6
Hartford                            Foundation,                            Inc.                                                                                      The         atherogenicity                                      of         7-dehydrocholesterol                                       has
American                            Journal                of         Clinical                  Nutrition                                                         411                                                                            Vol.       8,        July-A                 ugust                1960
412                                                                           Kritchevsky,                             Staple                     and              Whitehouse

                                                                             SCoA                                                 SCoA                                                       SC0A

                                            C-C-SCoA                   +     C0                                                   C=O                   Acetyl               C0A)            ?0

                                                     0                       C

                                                                                                                            C-C                                                        C-C_C_C=O

                                                                                                                                 0                                                         OH             OH

                                            2         Acetyl               CoA                                     Acetoacetyl                          CoA                      -Hydroxyl_                     p-Methyl
                                                                                                                                                                                 tllutaryl               C0A





                                                OH                                                    OH               OH

                                        Mevalonic                      acid               MVA-Pyrophosphate                                                         Fannesenic                  Acid

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                                            Squalene                                             Lanosterol                                                                  Cholesterol

                                                                                 FIG.       1.       Pathway                 of cholesterol                           biosynthesis.

been            attributed                       to            its         rapid                 conversion                          intothe              recent               emphasis                    on          the          role         of      unsaturated
cholesterol.’7                           Feeding                           lanosterol                           does                  notfat               as            a       hypocholesterolemic                                  agent.                     Alfin-
seem            to       affect           hepatic                     cholesterogenesis,                        how-                           Slater              and          co-workers’8                           have                reported                  that,         in
ever.                                                                                                                                          general,                  a    high           fat         diet          does            not            affect          hepatic
    The              effect        of       dietary                    fat          on           cholesterol                     bio- cholesterol                                synthesis.                    Opinion                     is      divided                   on
synthesis                   has      also              been           studied,                    especially                  with the                     comparative                                 effects                 of          diets               containing
                                                                                                                                               saturated                        fat             versus                     those                containing            un-
                                                     TABLE             I                                                                       saturated                        fat.              Three                      groups                 of     investiga-
       Effect          of     Fasting          and              of     Cholesterol                    Feeding               on                 torsm92’                  found             that           unsaturated                              fat         stimulated
                                   Cholesterol                       Synthesis
                                                                                                                                                                                                   TABLE              II

                                                                           Cholesterol                        Refer-                           Effect         of     Steroid               Feeding               on         Cholesterol                   Synthesis               in
  Species                   No.                 Diet
                                                                            Synthesis                          ence                                                                                the         Rat

       Rat                    3         Normal                                     1.00                           5                                                                                                             Choles-
                              5       Fasted,                                      0.08                           5                                     Compound                     Fed                    No.                  terol
                                          24             hr.                                                                                                                                                                  Synthesis
                              3       Fasted,                                      0.17                           5
                                          48             hr.                                                                                   None                                                             7                   1.00                        13
                              4       Fasted,                                      0.01                                                        Squalene                                                         2                   0.36                        13
                                          72 hr.                                                                                               Lathostenol                                                      4                   0.78                        13
       Dog                              Normal                                     1.00                           8                            7-Dehydrocholesterol                                             4                   0.74                        13
                              2         Cholesterol                                0.06                           8                            Coprosterol                                                      1                   0.32                        13
                                            (1%)                                                                                               Ergosterol                                                       1                   0.71                        13
       Rat                    2         Normal                                     1.00
                              9         Cholesterol                                0.03                            9                           None                                                             8                   1.00                        14
                                          (5)                                                                                                  Cholestenone                                                     5                   0.03                        14
       Rat                    6         Normal                                     1.00                          24                            Dehydroisoandrostenone                                           5                   0.14                        14
                              6         Cholesterol                                0.07                          24                            7-Dehydrocholestenol                                             3                   0.16                        14
                                            (1       (,))
                                                                                                                                               Lathosterol                                                      2                   0.08                        14
                                                                                              Cholesterol                                      Biosynthesis                                           and             Catabolism                                                                                                         413

                                                                                                                                                             TABLE                   III

                                                                                          Type         of     Dietary                    Fat          and               Cholesterol                         Synthesis                        the
                                                                                                                                                                                                                                         in Rat

                                                                                                                                       Dietary                         Fat

              .                                                   .                   .                Rapeseed                            Cottonseed                                      Coconut                                genated
          Normal                                              Corn               Oil                          .                                    .                                            .                      I                                                              Lard
                                                      .                                                    Oil                                   Oil                             1            011                            Cottonseed

                              .                                         1.00                                   .     .    .                             .     .    .                          0.07                                       .      .    .                                    .    .    .                             19
                  1(X)                                                  1.68                                  1.71)                                    .      .    .                          0.66                                       .     .     .                                    .    .    .                             20
                  tOo                                                   1.01                                   .     .    .                            .      .    .                          0.90                                       .     .     .                                    .    .    .                             21
                   ...                                                  1(X)                                   ...                                     1.43                                     ...                                     1.36                                          1.44                                        22
                         ..                                             1.00)                                  ...                                     ...                                      ...                                      ...                                          0.76                                        23

cholesterol                                      biosynthesis                                         more                     than              did                   satu- when                      added                     to            normal                           homogenates                                            they            also

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rated                fat.                        Two                   other                groups2223                            report                     no          such inhibit                                                                    28             The            site                of         the            starva-
differences                                 (Table                    III).                Fat-free                       diets            will               also              tion            block                  appears                                     to       be            between                            synthesis                        of
inhibit                                                                                      19,22             The                 data                      sug-               hydroxymethyiglutarate                                                                   and           formation                                 of squa-
gest          that                   accumulation                                           of cholesterol                                 in the                       liver                 29             Bucher                     and                        co-workers#{176}                             have                   investi-
causes                        a decrease                                   in cholesterol                                     biosynthesis,                                     gated
                                                                                                                                                                               at                       the                biosynthesis                                              of                 cholesterol                             in       the
least              in               this              one                  tissue.                          Extrahepatic                  biosyn-                               livers                 of          fasting                          and                  cholesterol-fed                             rats              using
thesis      may                             not              be affected       to                              the              same   degree.                                  acetate,                       mevalonate                                           or          squalene                             as         radioactive
    Alfin-Slater                                           et          suggested                                              that   cholesterol                                substrates.                                   They                             find                  that                  incorporation                                      of
levels                        in           the               liver                    might                    control                          cholesterol                     mevalonate                                 was                      not                    influenced                                      greatly                     by
biosynthesis.                                             Frantz                           and                co-workers24                            pro-                      starvation.                                Conditions                                           of             starvation,                        there-
posed                    an              inverse                              relation                       between                           total                    comi-fore,                    primarily                                affect                       some                         phase                  of        the           bio-
centration                                   of cholesterol                                      in liver   slices                                                of          thesynthetic                             pathway                                           preceding                                    utilization             of
rat and                            the        logarithm                                    of the rate    of hepatic                                                         bio-mevalonic                                 acid.                              In           experiments                          on              biosyn-
synthesis.                                 Gould,25                                   however,                                 believes                                that     thesis                  with                 liver                        homogenates                                   prepared                         from
this              suggestion                                          is        probably                             an          oversimplifica-                                cholesterol-fed                                         rats,                           Gould                       and               Popjak3m                        also
tion.                         In           cholesterol-fed                                   rats             he              found                   an               in-      found                       that             the                    block                       in            biosynthesis                  of           cho-
verse                linear                               relation                          between                            the    amount                                     of
                                                                                                                                                                                lesterol                     preceded                               formation                                  of         mevalonate.
free              cholesterol                                   in              the          liver                 and            the   logarithm
of        the                     biosynthetic                                        rate              in           this              tissue.                           ThisHormones
seems      more                                  logical      in view                                         of       Bucher                         and                Mc- Among                                  other                      physiologic                                              factors                   regulating
Garrahan’s                                       demonstration26                                                   that      the                      enzymes                   cholesterol                                biosynthesis                                          are                thyroid                       hormones,
required                            for           cholesterol                                 biosynthesis                                in the           liver estrogens            and                                                       pituitary                                          hormones.                 Choles-
are               found                           principally                                     in          certain                          particulate       terol     biosynthesis                                                              is reduced                                    during                   pregnancy32
fractions                                which       contain                                      cholesterol       in                                the               free. and              by            administration                                         of        estrogens,33                                   but           little
i.e.,     not                               esterified,                                          form.        Swell                                    and
                                                                                                                                                        co-                     work                  has          been               performed                            on         their                 precise                      mode
workers27                                  demonstrated                                               that                    cholesterol                                bio-of            action.
synthesis                                   is            sensitive                              to           fluctuations                 in               the                        The                  hypothyroid                                             state                     appears                        to          be          asso-
supply                              of            exogenous                                       cholesterol.                    The                   bio-                    ciated                  with                 a        general                               slowing                          of           all          metabolic
synthesis                                  of             cholesterol                                 from                    acetate-            ‘     I in
                                                                                                                                                           -C                   processes,                            includ                        ing                 synthesis                            of
lymph-flstula                                              rats                 was              much                    greater                      (70()                     Cholesterol
                                                                                                                                                                              per                                          biosynthesis                                         is accelerated                                       in hyper-
cent)                    than                    in          normal                          rats,              although                              liver                     thyroid
                                                                                                                                                                              and                              states                    and                        decreased                                   in          hypothyroid
plasma                            cholesterol                                 levels              were               about                the           same                   in
                                                                                                                                                                                conditions.3537                                         Since                             Schettler38                                     has             shown
both.                                                                                                                                                                           that       total                      body                     cholesterol                                         also              changes                       under
        Not               only                   are          liver                homogenates                                        from             starved                  the           influence                            of              the                  thyroid,                          we           might                    expect
rats              incapable                                   of              synthesizing                                     cholesterol,                                   hutthat                 the           increase                                  or          decrease                              of          liver              choles-
414                                                                                              Kritchevsky,                                   Staple                     and            Whitehouse

                                                                TABLE                 iv                                                                                                                                         TABLE                v
Effect                of     Thyroid                     Hormone                            on          Cholesterol                        Synthesis                  Effect                of        Radiation                        on            Cholesterol                            Synthesis                     from


                                                                                                                                                                               Normal                                                                                                  Reference

         Rat                                  1.0)0                        ...                             0.60                           37                                       1.00                                       1.95(2,5(X)r)                                                     46
      Rat                                     1.00)                     2.50                               0.82                           40                                       1.0()                                      4.20(3,750r)                                                      46
     Rabbit                                   1.00                      1.00                               0.75                           40                                       1 .00                                      3.95      (5,000      r)                                          46
     Guinea                  pig                  1.00                       -                             0.50                           40                                       1.00                                       3.30       (300    r)                                             47
     Rat                                      1.00                      2.03                               0.47                           43                                       1(X)                                       7.50      (900     r)                                             47
                                                                                                                                                                                   I .(X)                                   23.20)       (2,400)    r)                                          47
                                                                                                                                                                                   1.00                                       1.40      (400     r)                                             48

terol                 affects                   hepatic                   biosynthesis                                      of          this            sterol.
The                    most                   dramatic                                manifestation                                        of            hypo-
thyroidism                                    inhibiting                               cholesterol                               biosynthesis
has             been               observed                       in         man39                      (Table                   iv).                                        The             effect               of        glycolysis                          upon               cholesterol                            bio-

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           Fletcher                       and             Myant4#{176} observed                                              that                in          hy- synthesis                             must               also          be          noted.                        Bucher                   and            Mc-
perthyroid                                 rats            there                      is     an           increase                        in        choles- Garrahan26                                        have                shown                        that              the          biosynthetic
terol                 synthesis                          due            to              acetate                      but            not             due      capacity
                                                                                                                                                            to                                         of         liver               homogenates                       of            the         normal
mevalonate.                                     In         hypothyroid                                       rats                  incorpora-                         rat          could                be         abolished                              by      removal                        of       glycogen

tion                  of           acetate                   into                     cholesterol                             is          depressed,                  and            restored                          by         the              action                   of         hexose                   diphos-
but     that                         of mevalonate                                          is not.                         Again,                  a step phate.         Sipersteinhi         has   shown       that     reduced
preceding                              utilization                               of         mevalonate                            in              choles- triphosphopyridine            nucleotide,          generated          by
terol                      biosynthesis                                 is             affected.                             The                 rate      oxidation
                                                                                                                                                           of                of glucose      through       the     hexosemono-
formation                                of       mevalonate                                      thus               appears                       to          be phosphate
                                                                                                                                                                   a                                         pathway,                         is          required                      for          cholesterol

‘   ‘pacemaker”                                 for             the               entire                    biosynthetic                        se-               biosynthesis.                                    The                  lowered                             cholesterol                  bio-
quence.                                                                                                                                                               synthesis                       in fasted                       rats           may              also            be due,                  in part,
           The              effect                of      thyroid                           hormones                             upon                 excre- to                  lowered                      glycogen                        levels.                        Radiation                           causes
tion             of bile                  and            bile          acids                is an            important                             factor.            large              increases                        in      liver              glycogen                          levels            of          fasted
Friedman                                   and              co-workers4m43                                   have                   demon-                            rats52              but           not              in       normally                            fed         rats.47                      The            ex-
strated                       that              there             is         an            increased                        output                      of          biletremely                       high              rates                of           cholesterol                           biosynthesis
and              of          biliary                   cholesterol                                in       hyperthyroid                    rats.                        in rats                   exposed                        to          radiation                           suggest                      that            the
Conversely,                                   hypothyroid                                   rats                    excreted                            less          liver              glycogen                        level               is      only              one             of        several                  fac-
biliary                      cholesterol.                          These                     effects                   on          output                      of     tors           causing                      increased                          synthesis.                  Elevation                           of
bile                 have                been             confirmed44’45                                     and              an           increased                  liver              glycogen                       levels,               however,                           may             explain                  the
excretion                             of          bile            salts                    has           also              been                 noted                 stimulatory
                                                                                                                                                                      in                                          effect              of          corticotropin32                       on        choles-
hyperthyroidism.                                                                                                                                                      terol               biosynthesis.                               Depression                                 of         cholestero-
                                                                                                                                                                      genesis                    by         hypophysectomy53                                      might                 likewise                     be
Radiation                                                                                                                                                             attributed                             to        lowering                       of        glycogen                        levels,                since
           Radiation                            with                   x-rays                            causes                          increased
                                                                                                                                                                                                                                 TABLE                    VI
hepatic                        cholesterol                                biosynthesis           associated     .

                                                                                                                                                                       Factors                   Affecting                     Cholesterol            Synthesis                                  from            Acetate
with                       reduction                        of            liver      cholesterol           levels47’
                                                                                                                                                                                                                  and           from       Mevalonate
    (Table                    v).                 Further                         analysis                           reveals                    that                 in-
    corporation                                 of         acetate                     ‘         into               cholesterol                                is                                                                                                           Mevalo-                   Refer-
                                                                                                                                                                                   Effect                          Normal                  Acetate.C”
                                                                                                                                                                                                                                                                            nate.C”                    ence
    stimulated                             to        a greater                          extent                  by          radiation                          than
    is         the           incorporation                                       of         mevalonate2546                                            (Table
                                                                                                                                                                               Fasting                                  1.00                       0.02                       0.17                       30
    vi).                     Radiation                      will                       stimulate                        cholesterol                                            Cholesterol
                                                                                                                                                                                  feeding                               1.00                       0.000                      0.18                        mo
    synthesis                             even              in            hypophysectomized                                             rats.49                                Thyroid                                  1.00                       2.50                        1.00                      40
                                                                                                                                                                               Radiation                                1 .00                      5.60                       2.00                       30
    Evidently,                             the           effect                  of        radiation         is not                 depend-                                                                                                                                   4.23                       46
                                                                                                                                                                               Radiation                                1.00                       4.79
    ent          upon              the          pituitary                             gland.
                                                                                        Cholesterol                                   Biosynthesis                                   and                 Catabolism                                                                                                   415

                                                                TABLE                   VII                                                                        in          the               digitonide.60                                           It          was                concluded                                    that
            Factors                     Influencing                              Cholesterol                        Biosynthesis                                   cholesterol           biosynthesis                                                           is       inhibited                                    at           some
                                                                                                                                                                   stage       following         cyclization                                                            of squalene.                                                This
                       Increase                                                                       Decrease
                                                                                                                                                                   non-cholesterol                                          digitonin-precipitable                                                    material
                                                                                                                                                                   is      now                  known                      to           be          desmosterol                                       (24-dehydro-
            Thvn      )id hormones                                                      Cholesterol                   feeding
                                                                                                                                                                   cholesterol)    67
            Radiation                                                                   Starvation
            Triton       WR-1339                                                        Thyroidectomy                                                                  In summary,                                          the               biosynthesis                                       of         cholesterol
            Mn±,          Fe++                                                                                                                                     by        the           liver               is     under                    a type                       of        homeostatic                                    con-
                                                                                                                                                                   trol,           influenced                              by            changes                        in            the             levels                  of      free
                                                                                                                                                                    cholesterol                               and          /or           glycogen          in                                the              liver,   and
prefeeding                              a         diet                high               in         glucose                    or          starch                  to
                                                                                                                                                                    by withholding                                           of          the    appropriate                                                  coenzymes
hypophysectomized                                                      rats               will              restore                       hepatic                   (Table      vii).
cholesterogenesis                                        to           normal.54                                                                                        Frantz60       suggested                                               that              the               hon:eostatic                                     con-
                                                                                                                                                                   trol         mechanism                                  may                 depend                        on          the                presence                        of
Other                Factors
                                                                                                                                                                    “active”                        cholesterol,                                 as            opposed                            to         “inactive”
       A       few                    external,                             or           pharmacologic,                             factors                        cholesterol        bound       in                                            lipoproteins                                      or elsewhere.

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which                 influence                            cholesterol                                biosynthesis                                   should        Thus,       excess     dietary                                                 cholesterol,                                     for  instance,
also           be           mentioned.                                     Injection                        of       Triton               WR-                      would                   saturate                         all          available                               binding                          sites              and
1339                 (a               polymer                               of           p-isooctylpolyoxyethyl-                                                   result             in an                   excess               of “active”                                   cholesterol,                                which
phenol)                      markedly                                      stimulates                             cholesterol                               bio- then              inhibits                         biosynthesis.                              On            the            other                     hand,
synthesis55                                  in            rats.                        The                 biosynthetic                   step                    x-radiation                                could               promote                            formation                                   of         choles-
primarily                             affected                        here              also              appears                    to         be         that terol-binding                                  lipoproteins                                    (receptor                               molecules)
between                      acetate                       and                mevalonate.#{176}                                                                    in        the                liver,               thereby                              promoting                                   biosynthesis.
       Curran57                                   investigated                                      the           role              played                       by Triton                      WR-1339                             might                        likewise                              enhance                            re-
certain                metal                       ions               in      cholesterol                           biosynthesis                                  bymoval                  of       active                   cholesterol                                by              complex                             forma-
the          liver            of             the           rat.                    He              found             that                 chromous,                tion,             thus                 explaining                                its          accelerating                                         effect                on
chromic,                      manganous                                       and             ferric              ions             each           stimu-           cholesterol                                biosynthesis.                                   Most                 of            the              inhibi-
lated            biosynthesis,                                             whereas                     vanadous,                               vanadc,            tors    mentioned                                        have                in         common                            some                  action                  on
ferrous                    and               cobaltous                              ions             each                depressed                           bio- a stage        in                       the             biosynthetic                         pathway                                preceding
synthesis.                             The                effect                   of         vanadium                              is         exerted             formation                             of        mevalonate.
between                           the               synthesis                                 of       hydroxymethylglu-
tarate    and      of squalene.TM
    Since    the      initial   reports                                                            by Cottet                                    and              co- Cholesterol                                     is          metabolized                                     to         bile                 acids,               sex
workers59    .61) concerning       the                                                         hypocholesterolemic                                                 hormones                               and               adrenocortical                                              hormones                                   (Fig.
action                of      derivatives                                     of         2-phenylbutyric                           acid,              it            2).              Of           these,                   only                the              formation                                   of         bile           acid
has           been                    demonstrated                               that                these               compounds                                 need              be           considered                              here                 sinceit            has             been                     esti-
and            many                      of         their                    analogs6m63                                 all         inhibit                     themated                  that                froln               70          to             9(1      per              cent                 of         the          cho-
acetylation                             of          coenzyme                                   A.                Goldstein64                   has                  lesterol                     synthesized                                   daily                   is         converted                                  to        bile
found                      that                    most                       phenyl-substituted,                                     short-                        acids.697#{176}
chain                 fatty                   acids                    will              inhibit                   cholesterol                               bio-          Bile            acids                    enter                into                  the               enterohepatic                                        cir-
synthesis.                                                                                                                                                          culation                       but              are           continuously                          lost                in         the             feces
    A compound                                           commonly                                  designated                             as      MER-              by       incomplete                                   resorption                            through                               the          intestine.
29           (1  -     [4         -    diethyl              aminoethoxy
                                                                  -                                                 ]phenyl                -     1    -             Cholesterol                               may                also          be             removed                            from                 the          body
[p      -   tolyl]            -2-                  [p chlorophenyl]ethanol)
                                                     -                                                                               (tripa-                        by         direct                    elimination.                               It         is       excreted                              directly
ranol)                 has                   recently                            been                  reported                           to          inhibit into                   the            bile;                   it      then                      enters                    into                 the              entero-
cholesterol                             biosynthesis                                    in           intact                        rats               and           hepatic                      circulation                             together                            with                 the             bile             salts.
monkeys.65                               In              rats                maintained                                  on           this                drug      What                   is       not               reabsorbed                                     from                   the              intestine                           is
and           then                    given                acetate-C’4                                    there               is     no          diminu-            eliminated                                in          the            feces.                        If
                                                                                                                                                                                                                                                                     this               reabsorption
tion   of                  digitonin-precipitable                                               radioactivity           but                                         process                     is inhibited,                                 e.g.,            by           feeding                         roughage,7’
a marked                        decrease          in                             the           amount         of cholesterol                                        the        contributions                                of          the              biliary                  pathway                              for          re-
416                                                                                     Kritchevsky,                                       Staple                     and           Whitehouse

                                                                                                                                                                                            BILE                ACIDS

                                                                                                                                                                                            Sex            Hormones

                                                                                                                                                                                            Adrenocortjcal                            Hormones


                                                                                 FIG.         2.             Major                pathways                      of holesterol
                                                                                                                                                                 c                                 degradation.

moval                of          cholesterol                           as        such                   will          consequently                               acids,             being                  responsible                          for             scission                     of         the          bile
be           increased.                                   Cholesterol                               is              also                excreted,                acid           conjugates7’                             and            for          production                               of deoxy-
probably                         as          a       process                   of         desquamation                           of         the                  cholic                 acid               from                cholic                acid.76                           The               half-life
epithelial                        cells,                 through                     the                skin               and             into              theof       bile          acids               in      germ-free                       rats              is seven                     days,              but
intestinal                            tract.                  Quantitatively,                                  these                   path-                     in       normal                     (germ-full)                        rats              it                     I
                                                                                                                                                                                                                                                                     is only.S days.75
ways                of          direct                   elimination                               are              less           significant                   The               germ-free                             animals                          have                    higher                      serum

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for    disposal                       of cholesterol                                               in          mammals                                than cholesterol           levels.77       Bergstrom          and       Daniels-
formation                         of hepatic    bile                                acid.                                                                  son78      demonstrated            that      cholesterol        oxidation
       The            first               conversion                           of       cholic                      acid              was            dem- in vivo is controlled             via    a feedback          mechanism.
onstrated                            by           Bloch,                 Berg               and                 Rittenberg72                              inInjection         of     sodium        taurochenodeoxycholate
194:3            with                  rats      fed                   deuterium-labeled                                     choles-                       caused                       decreased                         excretion                             of      cholic       acid                       in          a
terol.              For                  conversion                        of cholesterol                                        to                 cholic bile-fistula                         rat.                      Thus,                    the                 concentration                                       of
acid           (the              principal                        bile           acid              found                    in         man)                  thebile            acids                supplied                    to       the                  liver              via         the             portal
body             must                  oxidize                   the           side           chain                   with                 removal               circulation                           influences                        the              rate               of         synthesis                          of
of       three             carbon                        atoms,                hydrogenate                                       the          double             bile           acids                by          the       liver.                     In             other                words,                     cho-
bond,               invert                  the           hydroxyl                     group                   at carbon                            atom lesterol                           degradation                        is        affected                            by          bile                acid
3,       and             introduce                         other                hydroxyl                             groups                    at          car- concentrations.
bon              atoms                       7           and 12.                 Bergstrom                                   and                    col-                This            conclusion                             was            also               reached                          by          Pihl79
leagues73                   have                  shown                that             hydroxylation                                          of the after                       he        studied                     effects               of      bile               acids                on         choles-
nucleus                    in         all         probability                           precedes                           oxidation                         ofterol              absorption,                              deposition                                  and              synthesis                          in
the          side           chain.                                                                                                                              rats.
   We have       already       observed                                                                 that               the             amount                       Other               workers803                                have                 demonstrated                           that
of free cholesterol      in the liver                                                       affects                   cholesterol                               feeding                   bile          acids             or bile salts                                may      raise                     serum
synthesis                       de          nozo.             We               might                      therefore                            pre-             cholesterol                            levels              and   inhibit                                hepatic                          choles-
sunie               that               cholesterol                             degradation                                   is         similarly               terol              biosynthesis,                                    presumably                                    by          inhibiting
governed                             by           the            concentration                          of           the              major                     further                 cholesterol                         catabolism                                 and             formation                           of
degradation                                 products                      in        the            liver                (feedback                              bile
                                                                                                                                                             ef-            acid.
fect).               Although                            there            are          less             data            available                          to           Using                  a          mitochondrial                        preparation                               of            the
justify                  such                an            assumptiomi,                                  the            experimental                            rat’s             liver               which                oxidizes                       cholesterol84                                  White-
evidence                        for         it      seems                no         less           convincing.                                                  house                   and                 Staple                    have                     shown                      that                 mito-
                                                                                                                                                                chondrial                            preparations                               from                    bile-fistula                                rats
Biliary                  Excretion                                                                                                                             (i.e.,     drained                                of circulating        bile      salts)                                                  oxidize
       Eriksson74                           measured                        excretion                           of         bile            salts,            incholesterol                            to         a greater      extent      than        do                                               control
hyper-,                  hypo-,                  and          euthyroid                                 bile-fistula                           rats.            animals.85                          They                also           found                     that               addition                         of
He        found                  the             least        excretion                            in        the           hypothyroid                          tauro-                 or          glycocholic                          acids           selectively                             inhibits
rats           and              niost                in      the            hyperthyroid                        rats.                      The                  oxidation                           of cholesterol,                                   but      not                        other         sub-
extent              of        excretiOn                          of       bile             salts                is         directly                        re- strates,                   by          this          system.                        These                     conjugates                             had
lated               to          cholesterol                              synthesis                             in          these                   condi- a     much       smaller       effect                                           on          the             oxidation                        of 3cx-,
tions.                    The               intestinal                         flora               are             known                      to       play 7 a-,    1 2a-trihydroxycoprostane                                                                       (Table                       viii),
an        important                                 role in           the           metabolism                                        of       bile             a       finding                    which                supports                     Bergstrom’s                                       hypoth-
                                                                                       Cholesterol                                            Biosynthesis                                              and                Catabolism                                                                                                  417

                                                           TABLE                   VIII                                                                                                                                                            TABLE                     IX

Oxidation                        of    Cholesterol                                     and     Tnihydroxycoprostane                                                               Oxidation                          of           Cholesterol-26-C’4                                    by              Mitochondria                           of
(THC)                 by         Liver     Mitochondnia                                 from    Normal         and       Bile-                                                                                                               Rat’s                   Liver*t
  Fistula                  Rats             and               Inhibition               by    Added        Bite      Salts*

                                                                                                                                                                                                                                                                    Per          Cent         of        Oxidationt
                                                                    Experiment                      1                Experiment                         2
                                                                                                                                                                                          Sex                                                                                             Diet
                                                                                                                                                                                                                ment     No.
                                                               Normal                   Fistula                   Normal                      Fistula

                                                                                                                                                                                                                                               Normal                             Unsaturated                          Saturated
  Per      cent       cholesterol                   oxi-
      dation                                                       10.7                   25.9                          7.3                     10.2
                                                                                                                                                                                    Mixed                              2                            15.6                                    1.7                                  9.6
                                                                                                                                                                                                                                                    15.2                                  17.4                                 17.6
 Per       cent             inhibition                   of                                         .             Tauro-                      Glyco-                                                                   3                            21.4                                    3.0                                15.5
                                                                                        Cholic                                                                                      Females                                                           5.3                                   6.6                                15.2
  oxidation                                                                                                        cholic                     cholic
 Cholesterol                                                                              81.5                      45.5                       49.7                                                                    2                              4.2                                    3.3                               12.0
  THC                                                                                     65.7                      27.0                        28.0                                                                                                21.0                                    1.9                                10.4
                                                                                                                                                                                                                       4                               1.3                                22.4                                 ii .8
                                                                                                                                                                                                                       5                            11.7                                    2.9                                  4.5
       * From:                  WHITEHOUSE,                    M.          W.      and             STAPLE,                     E.       Proc.            Soc.                       Males                                                             7.2                                   4.9                                  7.9
Exper.            Biol.         &     Mcd., 101:               439,         1959.’                                                                                                                                     2                            15.1                                  13.9                                 23.7
                                                                                                                                                                                                                       3                            15.0                                    3.0                                20.3
                                                                                                                                                                                                                       4                            11.1                                    2.8                                11.2

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esEstm6              that                   the                rate-determining                                          and                      feed-
                                                                                                                                                                                      *    From:                 KRITCHEVSKY,                           D.,          KOLMAN,                  R.         R.,         WHITEHOUSE.
back              sensitive                        step               in         formation                                    of         bile               acids                  is W.,
                                                                                                                                                                                  M.                    COTTRELL,                       M.         C.         and          STAPLE,F.               J.        Lipid             Res., 1: 83,
probably                            nuclear                        hydroxylation,                                 especially                                     at
                                                                                                                                                                                      t    All         values             corrected                 for         equivalent                         amounts                of      mitochondria
the            7a-         position.                                                                                                                                              (mg.           N).
                                                                                                                                                                                           Computed                        as     BaC         “Oz/cholesterol-26-C                             14#{149}
        The                natural                            mechanisms                            regulating                                          cho-
lesterol                        biosynthesis                              and                 metabolism                                      might
therefore                           be        represented                                         after                  the                  manner                              extent
                                                                                                                                                                                  of                       than                  do          mitochondria                               from                 rats              fed       rela-
Gould25                     (Fig.             3).                   The                rate-controlling                                 step             for                      tively                  saturated                                fat60                   (Table                   .   ix) Wilson                       and
cholesterol                                 degradation                                        is                probably                                    7a-hy- Siperstein9’                                                 showed                            that,                 when                     given                 a       single
droxylation.                                For               cholesterol                                   biosynthesis                              the                         tracer                   dose                  of         radioactive                                      cholesterol,                                rats             fed
rate           -controlling                                step                 lies             between                                 acetyl                        CoA lard                   excrete                        more               radioactivity                            as           bile          acid             than
and             mevalonate.                                                                                                                                                    do rats                           maintained                                     on               corn               oil.       Excretion                                   of
       The         hypocholesterolemic                                                   effect                    of          a diet                       rich               neutral                          steroids                          and            of              total               radioactivity                                      was
in        unsaturated                                  fat            has                been                    attributed                                      to            larger
                                                                                                                                                                             in-                         in the                  latter                 group,                      however.
creased                    excretion                          of          fecal             bile                 acid.87’88                              Lewis89
has            shown                  increased                            bile               acid                secretion                                 in         bile-
                                                                                                                                                                               Nicotinic                             Acid

fistula               human                       beings                    under                       the          influence                                   of         un-           This             in          vitro system                                        has               also                been                  used             to
saturated                           fat.                   From                   the             scheme                            presented,                                  it
                                                                                                                                                                               study                       the                  effects                       of           feeding                            nicotinic                             acid.92
would                      appear                          that                   cholesterol                      biosynthesis                                                We                find              a        marked                             enhancement                              of        cholesterol
should                     be              increased                              under                          these                    conditions.                          oxidation                                    in              rats                    fed                 nicotinic                               acid.                   This
This                 has             been                  shown                         to             be              so               in            rats.192’               finding                            supports                                    the                   initial                          suggestion                               of
Presumably,                                  catabolism                                  under                     these                      conditions                       Altschulm3                                  that                   the                mechanism                                       of          the                hypo-
far       exceeds     synthesis.                                                                                                                                               cholesterolemic                                              action                          of            nicotinic                               acid                 in-
        Using     the   mitochondrial                                                                   cholesterol                                     oxidase                volves                       enhancement                                    of             cholesterol                                  catabolism
system                     of        the          liver               described,84                                      we               have                    found (Tables                                   x          and               xi).                         Of           particular                                nutritional
that              mitochondria                                from                 the               livers                        of          rats                   fed      significance                                      is         the               fact                that                  nicotinamide,                    the
unsaturated                                 fat            oxidize                       cholesterol                                      to            a lesser usual                                   form                   in          which                         nicotinic                           acid               is      suppled

                                                  ACETATE                         9                      (?)-*                                  MVA              -*                       CHOLESTEROL                                -4-v                 BILE                   ACIDS

                                                  FIG.          3.              Schematic                             diagram                            suggesting                               control                       mechanisms                                  of          cholesterol
                                                  metabolism.            1, Feedback      mechanism                                                                                  sensitive liver
                                                                                                                                                                                             to      cholesterol                                                     concentra-
                                                  tion.       2, Feedback       mechanism       sensitive                                                                               to bile acid concentration.
418                                                                                         Kritchevsky,                           Staple                        and                 Whitehouse

                                                                                                                                           TABLE                X
Per             Cent         Oxidation                 of        Cholesterol-26-C’4                            and  Sodium                                    Pyruvate-2-C’4                  by          Mitochondnia                     of      Liver         of Rats                   Given
                                                                          Nicotinic                        Acid (12 mg/day)                                       in Their                    Drinking                    Water*

                                                                                                                                                   Per          Cent             Oxidation                of Substratest

 Experiment                                     Drinking
                                                                                                                                Males                                                                                                   Females
        no.                                       \\ater

                                                                                                  Cholesterol                                        Pvruvate                                                 Cholesterol                                        Pvrt          ‘ate

                  1                             Nicotinic                                                 25.8                         1                        8.3                                                   lost                                             lost
                                                Control                                                    8.8                         I                        1.4                                                     5.2                                              9.2
                  2                             Nicotinic                                                  6.6                                                  5.2                                                   19.3                                             22.1
                                                Control                                                    6.0                                                  9.2                                                   26.8                                             31.6
                  3                             Nicotinic                                                 22.2                                                20.3                                                    14.7                                             14.0
                                                Control                                                    14.0)                                              14.5                                                    18.6                                             21.7

       *    From:                 KRITCHEVSKY,                          D.,      \VHITEHOUSE,                        M.        \V. and             STAPLE,             E.              J. Lipid Res., 1: 154, 1960.92

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       t    Alt        values             are     corrected                      for          equivalent                  amounts            mitochondria
                                                                                                                                                  of                                 (mg.           N).

as          a         vitamin                   supplement,                       both                in      vivo and                     in              mals                  (Table                       xii).           Our          results                    suggest                      that
vitro has                       little           or              none            of           the          efficacy                    of         nico- this               effect                  is     due             to        enrichment                           of           natural                  co-
tinic                  acid               in          promoting                                hypocholesterolemia                                         factors                      normally                              present                in          the              particle-free
and               hepatic                 oxidation                            of cholesterol.                                                             supernatant                                   fractions                   of      the          liver,               which               stimu-
                                                                                                                                                           late             oxidation                            of           cholesterol.             Ferric                    ions           ap-
Metal                    Ions                                                                                                                              pear                 to           be          required                    for           hydroxylation                      of     the
       We              have              also         investigated                                  the       effects             of         metal cholesterol                                      nucleus.95
ions                   on          oxidation                               of              cholesterol             by           mito-                               Another                        consequence                               of      feeding                    these              metal
chondria                           of           the               rat’s                    liver.94                  Mitochondria                         ions             is        a possible                          reduction                   in         the          circulation                        of
from                   the          livers                  of          rats                fed            ferric,               cobalt                    or
                                                                                                                                                          bile         salts                 through                      the       enterohepatic                     circulation.
nickel                  ions             oxidized                      cholesterol                           to         a greater                          This
                                                                                                                                                         ex-                    would                    stimulate                      cholesterol                            oxidation                       by
tent                  than               did          preparations                          from             control                       ani-            the             liver.                       Siperstein,                        Nichols                    and              Chaikoff,96

                                                                                                                                           TABLE               XI
Per          Ceiit            Oxidation                     of        Cholesterol-26-C’4,                    Sodium               Pyruvate-2-C’’                            and         Sodium                  Octanoate-1-C’4                            by         Mitochondnia                        of
                                                                        Liver        from                 Rats      Fed           Nicotinic                         Acid             (0.75          per       incent

                                                                                                                                                   Per          Cent            Oxidation                 of Substratesf

                                                 Experiment                                                                     Males
            Substrate                                                                                                                                                                                                                   Females

                                                                                                    Nicotinic                                            Control                                                Nicotinic                                          Control

           Cholesterol                                            1                                         7.1                                                 1.9                                                   :34.8                                           22.5
                                                                  2                    I                  14.9                                                 2.2                                                    15.0)                                             13.9
                                                                                       I                  17.7                                                 4.4                                                     6.5                                               2.9

                                                                  4                                         .5.7                   I                            5.3
                                                                  5                                         2.1                                                 2.1
           P’ruvate                                               1                                         :3.1                                                1.9                           I
                                                                  2                    I                     1.7                                                1.4
           Octanoate                                              1                                       13.9                                                24.3                                                    21.5                                            25.1
                                                                  2                                       20.5                                                26.8                                                    :30.2                                           :35.6

       *    From:               KRIBCHEVSKY,                             D.,      WHITEHOUSE,                            M.       W. and                  STAPLE,                 E.          J.        Lipid             Res., 1:154,              1960.92

      t     All        values             are         corrected                   for          equivalent                     amounts                    of      mitochondria(mg.                       N).
                                                                                       Cholesterol                                          Biosynthesis                                         and                 Catabolism                                                                                               410

                                                              TABLE                    Xli                                                                                   vitamins,                               lipotropic                              agents,                       etc.)                  as           they               in-
Per          Cent                 Oxidation              of     Cholesterol-26-C’4                                            by        Fortified                            fluence                   the            serum                   cholesterol                              levels,                   presumably
                                   Mitochondria                             of         Rat’s           Liver*
                                                                                                                                                                             as a consequence                                             of altering    the relative                                                           rates              of
                                                                                                                                                                             hepatic    biosynthesis                                           and catabolism.
                                                   Super-                                  Per       Cent                 Oxidationt
 Mitochondria                                                                                    Experiment                                No.                                      Intestinal                             flora               may                 exert                  marked                        effects                  on
              fron                                                                                                                                                           the            serum                          cholesterol                                   levels                  of              animals                         fed
                                                    Rats                                                             II                           III                        cholesterol                                   plus                 various                           carbohydrates.                         l,

                                                                                                                                                                             Inasmuch                                as          the             intestinal                               flora              are               also              im-
            Fe-fed                                Fe-fed                                4.4                     21                               2 6                         plicated                         in      the           turnover                             of       bile             acids,                     their           role
                                                  Control                               1.4                     1.6                              2.0)                        in governing                                  cholesterol                                  homeostasis                                in         the          host
                                                  Nomie                                 1 .0                    0.        1                      0.5
            Co-fed                                Co-fed                                3.3                     3.6                              2.1
                                                                                                                                                                             should                      not            be         overlooked.
                                                  Control                               2.2                     2.5                              3.5
                                                  Nones                                 2.7                     0.1                              0.4
            Ni-fed                                Ni-fed                                2.8                     3.0                              1.8                                The                  formation                              of            cholesterol                               by              the               liver,
                                                  Control                               1.3                     4.1                              1.7
                                                  Nones                                 1.1                     Lost                             0. 7
                                                                                                                                                                             regulated                             by         a         type                 of          homeostatic                                    control,                        is
            C )ntr( )l                            Control                               1.3                     3.9                              0.9                         influenced                               by           the               hepatic                      level                of          free               choles-

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                                                  Fe-fed                                3.6                     3.9                              1.6                         terol               or            glycogen,                             or            both,                  and               by            the             avail-
                                                  Co-fed                                4.3                     4.5                              1.2
                                                  Ni-fed                                2.3                     4.6                              1.1                         ability                     of          the           proper                      enzymes.                                 Here                    the          fac-
                                                   Nonel                                0.2                     0.2                              (1.4                        tors               affecting                         the              hepatic                       biosynthesis                                       of      cho-
                                                                                                                                                                             lesterol                     are           detailed,                            including                           the              influence                        of
       NOTE:       Incubation           flask       contains        1 ml. mito-
                                                                                                  dietary                                                                                                 composition                                     and                 fasting.                            The               specific
chondrial         preparation,         1 imil. of cofactors,M                   5 ,nl.       of
boiled      supernatant           amid   5 ml.       of substrate            solution          in effects                                                                                              on        cholesterol                           synthesis         of                                  feeding                       cho-
tris[hvdroxvmethvljamninomnethane                          H Cl buffer,         pH      8.5.      lesterol,                                                                                                    various                         steroids,         saturated                                                    and            un-
All values            corrected        for    equivalent          amounts             of mito- saturated
                                                                                                                                                                                                                      fats               and                 thyroid                        hormone                                 are            re-
chondria                  (ing.          N).
       *    From:                   \\‘HITEHI)USE,                               M.            W.,         STAPLE,                        E.            and                  viewed                .          Also                considered                                    are               the              effects                       of
KRITCHEVSKY,                              I).          Arch.               Biochern.,                87 : 193,                          l900).                               radiation,                            glycolysis                            and             various                      pharmacologic
       t    Per            cent                 oxidation              computed                            as             BaC”03/clio-                                       agents.
lester                              14
       :1:10                (v/v              ) sucrose                     used                 instead                      of         l}oile(l               super-
                                                                                                                                                                                     In          the               degradation                                     of         cholesterol,                               the              chief
natant.                                                                                                                                                                       metabolic                            end            products                              are       bile            acids,                  although
                                                                                                                                                                             cholesterol                                   may                  also                be            converted                                    into                sex
basing                    their               work               on              the             known                         ferric                   chloride
                                                                                                                                                                             hormones                                and            adrenocortical                                          hormones.                                       The
precipitation                                     of          bile               salts n            vitro97                   prevented
                                                                                                                                                                             steps               involved                          in         the            degradation                                    of         cholesterol
hypercholesterolemia                                                  in         cholesterol-fed                                     cockrels
                                                                                                                                                                             to          bile            acids               are              reviewed,                           along                  with                  the           var-
by            feeding                           ferric                 chloride.                                 Beher,                                 Anthony
                                                                                                                                                                             ious               factors                      which                        increase                          or          decrease                            cho-
and               Baker98                       found,                      however,                             that                     cholic                     acid
                                                                                                                                                                             lesterol                    catabolism.                                         Since                degradation                                    of        cho-
absorption                               imm mice                     is         not             prevented                                  by           feeding
                                                                                                                                                                             lesterol                     depends                             on             the              levels               of            bile            salts                 in
ferric               salts.
                                                                                                                                                                             the            liver,                   any                factor                     which                    will              increase                           the
                                                                                                                                                                             turnover                           of         bile           acids                    will           also                accelerate                            cho-
       The                degradation                                 of           cholesterol                                     to          bile             acids lesterol                           catabolism                                and             may               in     turn                 lower                   serum
is         thus         seen              to        depend                  on          the           hepatic                             levels                    of       cholesterol.
bile              salts.                      Cholesterol                                    catabolism                                      is          acceler-
ated               under                  conditions                                  in         which                        bile             acid                 turn-
                                                                                                                                                                                    1.     BLOCH,                     K.      and       RITTENBERG,                             D.              On          time         utiliza-
over                 in            the            liver                is          increased.                    In                some                       in-
                                                                                                                                                                                                 ti()n          of      acetic                acid           for        cholesterol                     formation.                  J.
stances                     the            serum                     cholesterol                                levels                     also               reflect                         Biol. Chem., 145:625,             1942.
this              situation.                        Thus,                        germ-free                                    or           hypothy-                                2.     TAVORMINA,          P. A., GIBBS,      M. H. and HUFF,              J. \k’.
roid              animals,                        which                    exhibit                     longer                           half-lives                           of               The utilization          of -hvdroxv-fl-methvl-#{246}-valero
                                                                                                                                                                                              lactone      in cholesterol           biosynthesis.          J.    .1 ni.
bile          acid                also          have             higher                        serumn                     cholesterol                                 lev-
                                                                                                                                                                                          Ozern.                      Soc., 78: 4498, 1956.
els,              the              reverse                     being                         true               for                hyperthyroid
                                                                                                                                                                                   :3. LAXGDON,                        R. 0. and BLOCH,     K.                                            The          biosv,,tlmesis
animals.                                 Portman                           and                Stare99                         have                  reviewed                                     of squalene.                            J.          Biol.         chem.,              200:            129,            1950.
the           effects                    of       some                other                      factors                        (phytosterols,                                     4.      VAN                BRUGGEN,                   J.        T.,        HUTCHENS,                          T.         T.,          CLAy-
420                                                                                          Kritchevsky,                                                  Staple                      and           Whitehouse

            COMB,            C. K.,                CATHEY,                           W.          J. and                   WEST,                       E.       S.                               effect              of          the             nature                      of            dietary                       fat         on             synthesis
            The            effect            of         fasting                           upon                  lipogenesis                      in         the                                 of        cholesterol                                      from                  acetate-i-C”                           in          rat             liver
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