Lipoproteins: Synthesis, Transport and Metabolism by w0S3fBi3

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									-Today: Lipoproteins

-Friday: Quiz, b-oxidation and some paper discussion

-Monday: Dr. Neile Edens Guest Lecture
     -Read McGary review before lecture
   Transport of Fat: Lipoproteins

I. Chylomicrons
II. Triglyceride storage in adipose
III. VLDL, LDL, IDL, HDL
IV. Reverse Cholesterol Transport
V. Medical implications
VI. Nutritional regulation of lipoproteins



                 Stipanuk 351-364
                     Overview
• Transport dietary lipids from intestine to liver
  (exogenous)

• Transport lipids from liver to peripheral tissues
  (endogenous)

• Lipoproteins
   –   Core of TG and CE
   –   Surface of phospholipids and some cholesterol
   –   Apolipoproteins (regulators of LP metabolism)
   –   CM, VLDL, IDL, LDL, HDL


• Clinical importance for disease
                                                  Liver
Dietary TG
                           CE   Apo B48

             cholesterol
                                            Apo B48
                                                          CII
  FFA         FFA-FABP          TG
                                               TG/CE
 micelle
                                                          E
                                               CIII

                                            chylomicron
                                 ER/golgi


                    enterocyte




                                            Plasma
Chylomicron Assembly

-assembled in enterocyte golgi/ER

-Apolipoprotein (Apo) B organizes assembly
       -B48

- Requires phospholipids

-2 forms of apo B
    -B100, large- liver
    -B48, smaller – intestine

- Picks up apo C and apo E in plasma

- TG composition closely resembles dietary intake
I.    Synthesis of apoB

II.   ApoB associates with
      lipids

PDI (protein disulfide isomerase)
and MTP (microsomal TG transfer
protein) aid in LP folding and TG
addition

No MTP = No LP release
(a-betalipoproteinemia)

III. Lipoprotein release

IV. If not enough TG associates with
lipoprotein a protease removes apoB
and prevents its secretion

V. If lipoprotein is not properly formed
protease also can remove apoB and
prevent lipoprotein secretion
  Major Lipoproteins           Apolipoproteins           Density (g/mL)

  Apo B-48:     chylomicrons   C-II, C-III, E            <1.0

  Apo B-100:    VLDL           C-II, C-III, E             1.006
                IDL            E                 1.006-1.019
                LDL            none                       1.019-1.063

  Apo A-1      prebeta-HDL     none                      >1.21
               alpha-HDL       A-II                      1.063-1.21




Density inversely proportional to lipid content
Type     Association                Function

B48     Chylomicron                Lacks LDL recpt
                                   binding domain

B100    VLDL,IDL,LDL               Binds LDL recpt.

C-II    Chyl. VLDL, IDL, HDL       Activates LPL

C-III   Chyl. VLDL, IDL, HDL       Inhibits LPL

E       Chyl. Remnant, VLDL, IDL   Binds LDL recpt
        HDL

A-1     HDL                       LCAT activator
                               (lecithin:cholesterol
                                 acyltransferase)
Plasma
                                                                          TG
                  B48                                             FFA
                                                                          Oxidation
                              CII
                                                                          muscle
                   TG/CE                 Lipoprotein
           CIII                            Lipase

         chylomicron


                                    Lipoprotein                   B48      CII
                        FFA           Lipase
                                                                  TG/CE
                                                           CIII
              FFA                                                    E
                                                       Chylomicron remnant
                        G3P                                                      liver


          Triglyceride
                               adipose
          storage
Fat accumulation in adipose: High I/G (Fed)
                               Capillary endothelium
                                   (+)
       B48                                    insulin
                 CII
                        LPL                                       LPL deficiency?
        TG/CE
CIII


   chylomicron          FFA                             Glucose
                                         glut4
                                                                   (+)       Insulin
                                                                             regulated
                                                                             glucose
                       CoA                                                   transport
                                                  G3P
                             Fatty acyl CoA



                                               Triglycerides
             adipose
Fat accumulation in adipose: Low I/G (ketogenic)
                               Capillary endothelium
                                   (-)
       B48                                    insulin
                 CII
                        LPL
        TG/CE                                            FFA-albumin (oxidation)
CIII


   chylomicron          FFA                             Glucose

                                                                  (-)              Insulin
                                         glut4                                     regulated
                                                                                   glucose
                       CoA                                                         transport
                                                  G3P
                             Fatty acyl CoA



                                               Triglycerides
             adipose
Regulation of Lipoprotein Lipase


Fed state -   LPL synthesis (adipocytes)


Fasted/ -
                LPL synthesis (muscle)
exercise
state
Dietary factors affecting Chylomicron and Chylomicron remnant clearance



   -elevated postprandial lipoproteins and cardiovascular disease

   -Diets rich in PUFA can reduce postprandial TG response
       -compared to diets rich in SFA
       -Increased LPL activity = Increased TG clearance from CM
       -Preferential hydrolysis of PUFA-containing CM
       -Increased clearance of CMr
       -Human data are less convincing than animal studies

   -Omega 3 < Omega 6 < SFA
      -Not much work with MUFA although may be helpful (OLIVE OIL)
  Triglyceride Synthesis:
        Adipocytes
1.Source of glycerol 3-phosphate

2. Activate the fatty acid (CoA)

3. Synthesize the triglyceride
              O

  CH 2O       C
                  O


  CH      O       C
              O


  CH 2O       C
             Glycerol 3- phosphate

P O CH2 C CH2OH          Dihydroxyacetone phosphate
             O

                  NADH


    G3P DH

                  NAD



           H
P   O CH 2 C CH 2OH                         Glycerol
                           Glycerol
           OH              Kinase (liver)

Glycerol-3-phosphate
         Fatty Acid Activation


1. Fatty Acid + ATP         Fatty Acyl-AMP + PPi


2. Fatty Acyl-AMP + CoASH   Fatty Acyl CoA + AMP
             CH2 OH                     Glycerol 3 Phosphate Pathway
       HO       CH
             CH2 O         PO32-

  acylCoA
                      Glycerol 3 phosphate acyltransferase
 CoASH
                       O                                              Insulin and glucose
            CH2 O      C    R1                                        activate (4th reading?)
                                                                      Final and only
      HO    CH
                                                                      committed step in
            CH2 O      PO32-                                          TG synthesis
 acylCoA
                 Acyl 3-phosphate acyltransferase
CoASH
                             O                                                    O
       O         CH2 O       C     R1   H20    Pi     DGAT        O       CH2 O   C   R1
  R     C   O    CH                                          R2   C   O   CH      O
                                        phosphatase
                 CH2 O       PO32-                                        CH2 O   C   R3
                            2 Monoacylglycerol pathway
                               (intestinal enterocyte)

  O    CH2OH            O

R C O CH        +
                     R C SCoA
       CH2OH

      2MG



                            O                       O

            O       CH2 O C R            O    CH 2 O C R
        R C O CH                       R C O CH     O
                    CH2OH                     CH 2-O C R
            Hormones and Adipose Tissue

-Adipose tissue is not just a big fat depot

-Produces a number of hormones that regulate fat storage

1. Leptin – decrease food intake/increase energy utilization
        * Adequate fat store = release leptin = decrease food
          intake and increase energy utilization

2. Acylating stimulating protein (ASP)
     chylomicrons stimulate production of ASP
     similar anabolic effects as insulin (different mechanisms)
     Promote adipocyte glucose uptake and
     FA reesterification
Plasma
             Dietary Carbohydrate
                                            LIVER



                  glucose        pyruvate        Acetyl CoA

B48          LDL receptor        Acetyl CoA
         E                                           mitochondria
TG/CE
                                      TG
 CMr                                                       Cholesterol
                   cholesterol                             (endogenous)
                                              B100
                  (exogenous)

                                              CE/TG     VLDL
      FFA              FFA       TG




                                                                    VLDL
         Function of LDL receptor
•    Endocytosis of LDL and other LP
•    Release free cholesterol into liver
    1.   Incorporate into plasma membrane
    2.   Inhibit new LDL receptors
    3.   Inhibit cholesterol synthesis
    4.   Promote ACAT activity (FC -> CE)
•   Regulated by SREBP
    monitors free cholesterol
         Free cholesterol =   LDL receptors, chol. synthesis
                              ACAT
Plasma
          Dietary Carbohydrate
                                        LIVER



               glucose       pyruvate        Acetyl CoA


                             Acetyl CoA
                                                 mitochondria
               cholesterol
              (exogenous)         TG
                                                       Cholesterol
                                                       (endogenous)
                                          B100

                                          CE/TG     VLDL
    FFA             FFA      TG




                                                                VLDL
 From liver                Cholesterol.
                           In bile                  LIVER
                                            Endogenous cholesterol
           B100 E

                     CII
           CE/TG


           VLDL            B100 E
                                                   LDL receptor
                           CE/TG

                           IDL             E


                                            B100
               LPL                 TG      CE

     FFA                                  LDL        Extrahepatic tissue


muscle     adipose                                     LDL receptor
      HDL and Reverse Cholesterol
              Transport
                                            Lipid poor AI are the
    Liver and small intestine               smallest HDLs (liver and SI)

                                            Discoidal HDL are produced
Lipid poor AI                               by the action of LCAT
 (pre HDL)                                  (esterify cholesterol)

                                spherical   Spheroidal HDLs are
                                            produced by the further action
Cholesterol                                 of LCAT and CETP (tranfer
                                            cholesterol to LP for TG)
   LCAT
                                LCAT        HDLs pick up apoproteins from
                                CETP
                                            other LP

                Discoidal HDL
 HDL picks up free cholesterol from                   Extrahepatic tissue/cells
peripheral tissues and converts it into
          cholesterol esters
                                                         Cholesterol esters
                    LCAT                                       acat
                                                        Free cholesterol


                                               Cholesterol and lecithin (phospholipid)
           Extracellular space
                                                                              LCAT
                                      AI HDL              Discoidal HDL

                                               AI
                                 1
     HDL/Cholesterol
     To liver                                                      2       CETP
                                      3
                                                                Cholesterol to IDL,
                          Adrenal, gonadal                      LDL and VLDL
  PLASMA
CETP exchanges cholesterol esters in HDLs for triglycerides in VLDLs and
chylomicrons.


                              VLDL
                                                   CE

                                                CETP
                 FFA
                        LPL                    TG


Liver                          IDL             TG
(LDL receptor)                                                         HDL
                                              CETP
                                              CE


                        LPL
                 FFA                            TG
                                                CETP
Liver
                                                        CE
(LDL receptor)
                              LDL
                                                      Extrahepatic tissue/cells

  1. LCAT deficiency?
  2. CETP deficiency?                                          CE
  3. apo AI deficiency?                                        ACAT
                                                         FC


                                               Cholesterol and lecithin (phospholipid)
         Extracellular space
                                                                             LCAT
                                   Pre b HDL              Discoidal HDL


                                               AI
                               1
  HDL/Cholesterol
  To liver                                                          2     CETP
                                    3
                                                                Cholesterol to IDL,
                        Adrenal, gonadal                        LDL and VLDL
PLASMA
Reverse cholesterol transport: HDLs return cholesterol to liver


                                                LCAT
                                    FC
       Free                     Discoidal HDL              CE   Spherical HDL
       cholesterol



                                         TG
   Peripheral tissue   AI HDL
                                                    CETP



                       IDL CE        VLDL CE                          VLDL TG




       liver
                          Bile acids/Free cholesterol
                                                                       LDL


              Dietary fat       Bile salts   Endogenous
                                             Cholesterol
                                                                             extrahepatic
  small                                      Exogenous                       tissue
  intestine                                  cholesterol


                                                                                    HDL
                             chylomicrons
chylomicrons                 reminants
                                                           VLDL

                                                                                    IDL




    capillaries

                            Lipoprotein Lipase             Lipoprotein Lipase
                                                 FFA                             FFA
                                                               Adipose, muscle
  Dietary Regulation of Lipoprotein
             Synthesis
Chylomicron Synthesis                     VLDL Synthesis (Liver)




     Chylomicron                         VLDL    (+)
                             High CARB                  FA/TG
                             Insulin

                   (+)
                                                       Acetyl CoA
                          Dietary Fat

  Intestinal Epithelium
                                         (+)
                                                        Glucose
 Atherogenic Particles

                                                  Apolipoprotein B
        MEASUREMENTS:
                                                  Non-HDL-C




        VLDL              VLDLR              IDL        LDL    Small,
                                                               dense
                                                                LDL
            TG-rich lipoproteins

Thanks to Lipids Online: http://www.lipidsonline.org/
      Hypertriglyceridemia and CHD Risk:
          Associated Abnormalities

 Accumulation of chylomicron remnants
 Accumulation of VLDL remnants
 Generation of small, dense LDL-C
 Association with low HDL-C
 Increased coagulability
  -  plasminogen activator inhibitor (PAI-1)
  -  factor VIIc
  - Activation of prothrombin to thrombin
Relationship between HDL/LDL and heart disease:
                  One Theory

      Monocyte (white blood cell)
                                            Cholesterol to liver

                                   LDL
                                                    vascular endothelium

                       (+)
   differentiate             Oxidized LDL
                                                     Arterial intima

                   Macrophage

             LDL (+)     (-) HDL




            Foam cells (fatty streak)
   Alcohol Increases HDL-C Level
• Alcohol increases HDL-C level in a dose-dependent
  manner.
• Half bottle of wine per day (39 g alcohol) for 6 weeks
  significantly increased mean HDL-C level by 7 mg/dL
  in 12 healthy subjects.1
  – Wine intake did not significantly affect Total-C,
    Total-TG, or LDL-C.1
• One beer per day (13.5 g alcohol) for 6 weeks
  significantly increased mean HDL-C level by 2 mg/dL
  in 20 healthy subjects.2
  – Beer intake did not significantly affect LDL-C,
    VLDL-C, TG, or apolipoproteins.

  1. Thornton J et al. Lancet 1983;ii:819–822
  2. McConnell MV et al. Am J Cardiol 1997;80:1226–1228
  Postprandial Changes in Plasma
         Lipid Metabolism
    Fat storage via LPL
    Transfer of cholesterol from cells into plasma
    reverse transport of cholesterol from peripheral tissue to liver

    Exchange of cholesterol for VLDL TG in HDL (CETP)

    LCAT activity = esterification of free cholesterol (HDL)



These postprandial changes are beneficial in maintaining
whole body homeostatsis of glycerides and cholesterol
    Cholesterol levels are regulated
•   1. Synthesis : HMG CoA reductase
•   2. LCAT/ACAT : Free cholesterol
•   3. LDL receptor levels
•   4. Reverse cholesterol transport
•   5. Dr. Allred will discuss further

								
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