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					    Lipid Transport

Lipoprotein Structure, Function,
        and Metabolism
                     Introduction
• Fats are triacylglycerols containing saturated fatty acids
  - solid at room temp
  - usually from animal source (however, coconut & palm oil are
  saturated).

• Oils are triacylglycerols containing mono- or polyunsaturated fatty
  acids
  - liquid at room temp
  - usually from plant sources (however, fish oils are
  polyunsaturated).

• Phospholipids are triacylglycerols that have had a FA replaced with
  a phosphate linked FA group.

• The major dietary sterol is cholesterol.
                  Health issues
• Excessive dietary fat intake is associated with obesity,
  diabetes, cancer, hypertension and atherosclerosis.

• Not more than 35% of energy intake should come from fat.
  Saturated fat should not make up more than 15% of the total fat
  intake.

• Omega-3 fatty acids (20 carbons) from fish may protect against
  atherosclerosis. American Heart association recommends 2-3
  fish meals per weak. Fish oil supplements should be avoided
  because they may be contain concentrated toxins accumulated
  by the fish.
          FUNCTIONS OF LIPIDS:
• Major components of cell membranes.

• Required to solubilise fat soluble vitamins

• Biosynthetic precursors (e.g. steroid
  hormones from cholesterol)

• Protection (e.g. kidneys are shielded with fat
  in fed state)

• Insulation
           LIPID DIGESTION
• Stomach - lingual lipase and gastric lipase attack
  triacylglycerols and hydrolyse a limited number of
  FA.

• Small Intestine - acid chyme (stomach contents)
  stimulates mucosa cells to release hormone
  (choleocystokinin) which stimulates gall bladder and
  pancreas to release bile and digestive enzymes
  respectively (bile acids help emulsify fat droplets
  thus increasing their surface area).

• Other mucosa cells release secretin which causes
  pancreas to release bicarbonate rich fluid to
  neutralise chyme.
Enzymic digestion of lipids in small intestine

                                 2-monoacylglycerol
• Enzymic digestion generates more polar products that form
  mixed micelles of free fatty acids, 2-monoacylglycerol,
  cholesterol & bile salts that are adsorbed (except bile salts
  which pass through to ileum – see later).

• Once adsorbed fatty acids and 2-monoacylglycerol are
  recombined to form triacylglycerol.

• Triacylglycerol + cholesterol + phospholipid + proteins form a
  lipoprotein complex called a chylomicron which transports the
  lipids in the circulation.
                           Lipid transport in the circulation
Lipids are insoluble in plasma. In order to be transported they are combined
with specific proteins to form lipoproteins:


                                                 Proteins (apoproteins)


                      HO




                              O                            Non polar lipids in core
                              R
Cholesterol                                             (TAG and cholesterol esters)
                                  O

                                  R
                                            HO
                                            H




                     HO




Apoproteins are only weakly associated with a particular lipoprotein and are
easily transferred to another lipoprotein of a different class. Apoproteins have
various functions including:
• Structural role
• Binding sites for receptors
• Activators or co-enzymes for enzymes involved with lipid metabolism
                            The five classes of lipoprotein
                     (all contain characteristic amounts TAG, cholesterol, cholesterol esters,
                                          phospholipids and apoproteins)

                                                  Diameter                                Major apoliproteins
                               Class                (nm)        Source and function
                           Chylomicrons             500        Intestine. Transport of     A, B48, C(I,II,III) E
                               (CM)                                 dietary TAG
Increasing density




                          Very low density          43          Liver. Transport of        B100, C(I,II,III) , E
                            lipoproteins                     endogenously synthesised
                               (VLDL)                                   TAG

                      Low density lipoproteins      22       Formed in circulation by             B100
                              (LDL)                          partial breakdown of IDL.
                                                              Delivers cholesterol to
                                                                peripheral tissues
                      High density lipoproteins      8         Liver. Removes “used”        A, C(I,II,III), D, E
                               (HDL)                          cholesterol from tissues
                                                                 and takes it to liver.
                                                             Donates apolipoproteins to
                                                                    CM and VLDL
                              Apolipoproteins


   Provide structural stability to Lp
   Serve as ligands for interaction w/Lp receptors that help determine
    disposition of individual particles
   Act as cofactors for enzymes involved in plasma lipid and Lp
    metabolism
          There are many types of apolipoproteinsa
Apoprotein    Lipoproteins          Function(s)
Apo B-100 VLDL, IDL, LDL            1) Secretion of VLDL from liver
                                    2) Structural protein of VLDL, IDL, and HDL

                                    3) Ligand for LDL receptor (LDLR)


Apo B-48      Chylomicrons,         Secretion of chylomicrons from intestine;
              remnants              lacks LDLR binding domain of Apo B-100
Apo E         Chylomicrons, VLDL,   Ligand for binding of IDL & remnants to
              IDL, HDL              LDLR and LRP
Apo A-I       HDL, chylomicrons     1) Major structural protein of HDL
                                    2) Activator of LCAT

Apo A-II      HDL, chylomicrons     Unknown
Apo C-I       Chylomicrons, VLDL,   Modulator of hepatic uptake of VLDL and
              IDL, HDL              IDL (also involved in activation of LCAT)
Apo C-II      Chylomicrons, VLDL,   Activator of LPL
              IDL, HDL
Apo C-III     Chylomicrons, VLDL,   Inhibitor of LPL activity
              IDL, HDL
          Plasma Lipoproteins
          Structure

   LP core
       Triglycerides
       Cholesterol esters
   LP surface
       Phospholipids
       Proteins
       cholesterol
Lipoprotein    Density       Diameter    Protein % Phosphol   Triacylglycerol
class          (g/mL)        (nm)        of dry wt ipid %     % of dry wt
HDL            1.063-1.21    5 – 15      33        29         8


LDL            1.019 –       18 – 28     25        21         4
               1.063

IDL            1.006-1.019   25 - 50     18        22         31


VLDL           0.95 –        30 - 80     10        18         50
               1.006

chylomicrons   < 0.95        100 - 500   1-2       7          84




       Composition and properties of human lipoproteins

most proteins have densities of about 1.3 – 1.4 g/mL and lipid aggregates usually
have densities of about 0.8 g/mL
             Plasma Lipoproteins
             Classes & Functions
   Chylomicrons
       Synthesized in small
        intestine
       Transport dietary lipids
       98% lipid, large sized,
        lowest density
       Apo B-48
            Receptor binding
       Apo C-II
            Lipoprotein lipase activator
       Apo E
            Remnant receptor binding
Chylomicron
   formed through extrusion of resynthesized
    triglycerides from the mucosal cells into the
    intestinal lacteals
   flow through the thoracic ducts into the
    suclavian veins
   degraded to remnants by the action of
    lipoprotein lipase (LpL) which is located on
    capillary endothelial cell surface
   remnants are taken up by liver parenchymal
    cells due to apoE-III and apoE-IV isoform
    recognition sites
          Chylomicron Metabolism

   Nascent chylomicron
    (B-48)
   Mature chylomicron
    (+apo C & apo E)
   Lipoprotein lipase
   Chylomicron remnant
       Apo C removed
       Removed in liver
             Plasma Lipoproteins
             Classes & Functions
   Very Low Density
    Lipoprotein (VLDL)
       Synthesized in liver
       Transport endogenous
        triglycerides
       90% lipid, 10% protein
       Apo B-100
            Receptor binding
       Apo C-II
            LPL activator
       Apo E
            Remnant receptor
Plasma Lipoproteins
Classes & Functions
   Intermediate Density Lipoprotein
    (IDL)
       Synthesized from VLDL during VLDL degradation
       Triglyceride transport and precurser to LDL
       Apo B-100
            Receptor binding
       Apo C-II
            LPL activator
       Apo E
            Receptor binding
             Plasma Lipoproteins
             Classes & Functions
   Low Density
    Lipoprotein (LDL)
       Synthesized from IDL
       Cholesterol transport
       78% lipid, 58%
        cholesterol & CE
       Apo B-100
            Receptor binding
LDL molecule
         VLDL Metabolism

   Nascent VLDL (B-100) + HDL (apo C & E) = VLDL
   LPL hydrolyzes TG forming IDL
       IDL loses apo C-II (reduces affinity for LPL)
   75% of IDL removed by liver
       Apo E and Apo B mediated receptors
   25% of IDL converted to LDL by hepatic lipase
       Loses apo E to HDL
             Plasma Lipoproteins
             Classes & Functions
   High Density Lipoprotein
    (HDL)
       Synthesized in liver and intestine
       Reservoir of apoproteins
       Reverse cholesterol transport
       52% protein, 48% lipid, 35% C &
        CE
       Apo A
            Activates lecithin-cholesterol
             acyltransferase (LCAT)
       Apo C
            Activates LPL
       Apo E
            Remnant receptor binding
Functions of HDL
   transfers proteins to other lipoproteins
   picks up lipids from other lipoproteins
   picks up cholesterol from cell membranes
   converts cholesterol to cholesterol esters via
    the LCAT reaction
   transfers cholesterol esters to other
    lipoproteins, which transport them to the liver
    (referred to as “reverse cholesterol transport)
         LDL Metabolism
   LDL receptor-mediated
    endocytosis
       LDL receptors on „coated
        pits‟
            Clathrin: a protein polymer
             that stabilizes pit
       Endocytosis
            Loss of clathrin coating
            uncoupling of receptor,
             returns to surface
       Fusing of endosome with
        lysosome
            Frees cholesterol & amino
             acids
Coordinate Control of Cholesterol
Uptake and Synthesis
   Increased uptake of LDL-
    cholesterol results in:
   inhibition of HMG-CoA reductase
       reduced cholesterol synthesis
   stimulation of acyl CoA:cholesterol acyl
    transferase (ACAT)
       increased cholesterol storage
       TG + C -> DG + CE
   decreased synthesis of LDL-receptors
       “down-regulation”
       decreased LDL uptake
Heterogeneity of LDL-particles
   Not all LDL-particles the same
       Small dense LDL (diameter <256A)
       Large buoyant LDL (diameter >256 A)
       Lamarche B, St-Pierre AC, Ruel IL, et al. A prospective,
        population-based study of low density lipoprotein particle
        size as a risk factor for Can J Cardiol 2001;17:859-65.
            2057 men with hi LDL, 5 year follow-up
            Those with elevated small dense LDL had RR of 2.2 for IHD
             compared to men with elevated large buoyant LDL
       Detection expensive
       Treatment for lowering small dense LDL similar to lowering
        all LDL (diet, exercise, drugs)
            Some drugs (niacin, fibrates) may be more effective at
             lowering small dense LDL.
    LDL Particle Size and Apolipoprotein B Predict Ischemic
         Heart Disease: Quebec Cardiovascular Study

6
                                    6.2
5
                                (p<0.001)
4
3
                                                 Apo B
2                   2.0
                                                >120
1                                               mg/dl
              1.0                 1.0
0                                              <120
           >25.64                              mg/dl
                               <25.64
           LDL Peak Particle Diameter
                     (nm)
HDL Metabolism: Functions
   Apoprotein exchange
       provides apo C and apo E to/from
        VLDL and chylomicrons
   Reverse cholesterol transport
        Reverse cholesterol transport

   Uptake of cholesterol
    from peripheral tissues
    (binding by apo-A-I)
   Esterification of HDL-C
    by LCAT
       LCAT activated by apoA1
   Transfer of CE to
    lipoprotein remnants
    (IDL and CR) by CETP
   removal of CE-rich
    remnants by liver,
    converted to bile acids
    and excreted
Cholesterol and lipid transport by
lipoproteins
Cholesterol and lipid transport by
lipoproteins
The LDL receptor
   characterized by Michael Brown and Joseph
    Goldstein (Nobel prize winners in 1985)
   based on work on familial
    hypercholesterolemia
   receptor also called B/E receptor because of
    its ability to recognize particles containing
    both apos B and E
   activity occurs mainly in the liver
   receptor recognizes apo E more readily than
    apo B-100
Atherosclerosis
   hardening of the arteries due to the
    deposition of atheromas
   heart disease is the leading cause of
    death
   caused by the deposition of cholesteryl
    esters on the walls of arteries
   atherosclerosis is correlated with high
    LDL and low HDL
Factors promoting elevated blood
lipids
   age
      men >45 years of age; women > 55 years of age

   family history of CAD
   smoking
   hypertension >140/90 mm Hg
   low HDL cholesterol
   obesity >30% overweight
   diabetes mellitus
   inactivity/ lack of exercise
HMG CoA reductase
   3 different regulatory mechanisms are
    involved:
          covalent modification: phosphorylation by
           cAMP-dependent protein kinases inactivate the
           reductase. This inactivation can be reversed by
           2 specific phosphatases
          degradation of the enzyme – half life of 3 hours
           and the half-life depends on cholesterol levels
          gene expression: cholesterol levels control the
           amount of mRNA
                    HO                O
                                                                       HO                      O

                                O
            O                                                                            O
                                                            O

                O
H3C         H        H                                             O
                                CH3             H3C         H           H
                                                                                         CH3



                                                      H3C
            MEVASTATIN
                                                            LOVASTATIN (MEVACOR)


                           HO               O
                                                                                    HO
                                                                                                   COOH
                                      O
                                                                                                   OH
                 O
                                                                            O

                       O
                                                                                O
      H3C        CH3       H
                                                            H3 C            H       H
                                      CH3
                                                                                                   CH3



                                                                   HO
                SIMVASTATIN (ZOCOR)
                                                                            PRAVASTATIN (PRAVACHOL)
HMG CoA reductase inhibitors
   Precaution:
          mild elevation of serum aminotransferase
           (should be measured at 2 to 4 month intervals)
          minor increases in creatine kinase (myopathy,
           muscle pain and tenderness)
          do not give during pregnancy
    Low-Density Lipoproteins (LDLs)
   “Bad” cholesterol
   Delivers cholesterol to cells
   Can increase build-up of plaque
   High levels of LDL associated with
    increased risk for cardiovascular disease
     High-Density Lipoproteins (HDLs)
   “Good” cholesterol
   Made by liver
   Circulates in the blood to collect excess
    cholesterol from cells
   Returns cholesterol to liver for excretion in
    bile
   Highest protein content
Overview of Lipoproteins
LDL
   = Low Density Lipoprotein
   Made in: the Liver as VLDL
   Arise from: VLDL once it has lost a lot of its
    TG‟s
   Secreted into: the bloodstream
   Rich in: Cholesterol
   Function: Deliver cholesterol to all body cells
    HDL
   = High Density Lipoprotein
   Made in: the Liver and Small Intestine
   Secreted into: the bloodstream
   Function: Pick up cholesterol from body
    cells and take it back to the liver =
    “reverse cholesterol transport”
   Potential to help reverse heart disease
Cardiovascular Disease (CVD)
   Main type of CVD is Atherosclerosis
    (AS)
   Endothelial dysfunction is one of
    earliest changes in AS
   Mechanical, chemical, inflammatory
    mediators can trigger endothelial
    dysfunction:
       High blood pressure
       Smoking (free radicals that oxidatively
        damage endothelium)
       Elevated homocysteine
       Inflammatory stimuli
A Healthy Endothelium
produces:
 PGI2
 NO




                        Maintaining an
                        anti-coagulant,
                        anti-thrombotic
                        surface
A Dysfunctional Endothelium
has decreased:
 PGI2
 NO




                                                  Increased:
                                           pro-inflammatory
                                                  molecules:
                                                   MCP-1
                                                 TNFa
                                               VCAM-1
                              Shifting to a
                              pro-coagulant, pro-
                              thrombotic surface
Pro-Inflammatory Molecules
   Chemokines = monocyte chemoattractant
    protein 1 (MCP-1)
   Inflammatory cytokines = tumor necrosis
    factor a (TNFa)
   Adhesion molecules = intercellular
    adhesion molecule 1 (ICAM-1), vascular cell
    adhesion molecule 1 (VCAM-1)
   Overexpression of all these inflammatory
    mediators is commonly seen in
    atherosclerotic lesions.
Endothelial Dysfunction
( endothelial activation, impaired endothelial-dependent
vasodilation)

     endothelial synthesis of PGI2
    (prostacylcin), & NO (nitric oxide)
       PGI2 = vasodilator, platelet adhesion/aggregation
       NO = vasodilator, platelet & WBC (monocyte) adhesion


     Adhesion of monocytes onto endothelium
    --> transmigration into subendothelial space
    (artery    wall) --> change to macrophages

   Endothelial dysfunction --> increased flux of
    LDL into artery wall
Oxidation of LDL (oxLDL)
   Oxidation = process by which free radicals (oxidants)
    attack and damage target molecules / tissues
   Targets of free radical attack:
       DNA                     - carbohydrates
       Proteins                - PUFA‟s>>> MUFA‟s>>>>>
        SFA‟s



   LDL can be oxidatively damaged: PUFA‟s are oxidized
    and trigger oxidation of apoB100 protein --> oxLDL


   OxLDL is engulfed by macrophages in subendothelial
    space
Atherosclerotic Plaque
   Continued endothelial dysfunction (inflammatory
    response)
   Accumulation of oxLDL in macrophages (= foam
    cells)
   Migration and accumulation of:
       smooth muscle cells,
       additional WBC‟s (macrophages, T-lymphocytes)
       Calcific deposits
       Change in extracellular proteins, fibrous tissue formation

   High risk =  VLDL (TG)                  LDL        HDL
Antioxidant Defense Systems
   1. Prevent oxidation from being
    initiated

   2. Halt oxidation once it has begun

   3. Repair oxidative damage
    Antioxidant Mechanisms
   Antioxidant vitamins (vitamins C, E,
    carotenoids)

   Flavanoids and other phytochemicals

   Antioxidant enzyme systems
       Minerals required: Mn, Cu, Zn, Se
Factors Associated with CVD

   Genetic Variables
       Being male
       Being post-menopausal female
       Family history of heart disease before the
        age of 55 (some are associated with
        genetic defects in LDL receptors)
Factors Associated with CVD
• Dietary
   1. Elevated levels of LDL
   --More LDL around to potentially oxidize and accumulate in
       artery wall
   2. Low levels of HDL
   --HDL carries cholesterol from artery walls back to the liver
   3. Low levels of antioxidant vitamins
   --Vit. E, Vit. C, Beta-carotene
   4. Low levels of other dietary antioxidants
   --Phenolics, flavanoids, red wine, grape juice, vegetables,
       fruits
Factors Associated with CVD
   High blood pressure
        • Damages the artery wall allowing LDL to enter
    the wall
           more readily
    Cigarette Smoking
           Cigarette smoke products are oxidants and can
            oxidize LDL
           Cigarette smoking compromises the body‟s
            antioxidant vitamin status, especially Vit. C
           Damages the artery wall
    Activity Level
           Exercise is the most effective means of raising
            HDL levels
    Obesity
Homocysteine Levels
   Normal byproduct of certain metabolic
    pathways
   Normally metabolized to other products
   Elevated levels cause damage to artery walls
    = increased the oxidation of LDL
   Elevated homocysteine levels are significantly
    correlated with increased risk to heart
    disease.
   Vitamins B6, B12, and Folic acid normalize
    homocysteine levels.
                              Diet

                           Methionine (a.a.)

             Enzymes
             B12, Folate


    Homocysteine                                     SAM
     Enzym                                            1. Norepinephrine
       e                                              2. Guanidinoacetate
       B6                                             3. Serotonin
                                                      4. Serine
  cysteine                               CH
                                               1. Epinephrine
                               SAH       3
                                               2. Creatine
                                               3. Melatonin
sulfate                                        4. Choline
Dietary/Lifestyle Prevention/Intervention of
Heart Disease
   Maintain           Platelet        Decrease           Increase        Increase
  Endothelial         Activity          LDL                HDL           Antioxida
   Function                                                                 nts
  High Blood     w-3 PUFAs        Saturated Fat      MUFA/           MUFA/
 Pressure          w -6 PUFA                          PUFA               w -6 PUFA

                                  Cholesterol        w-3 PUFAs       Vegetables
 Homocysteine     Phytochemicals                       (fish)
 B6, B12, Folic
 Acid
 Phytochemical   Aspirin           w-3 oils (fish)    Exercise        Fruits
 s
 Stop smoking                       Fiber             Stop smoking      Stop smoking


                                    Trans Fats        Body weight if
                                                       overweight


                                                        Fiber
 Know Your Lipid Profile
Fasting Blood Level   Ideal, Healthy Level

  Total Cholesterol      < 200 mg/dl

  LDL-Cholesterol        < 100 mg/dl

  HDL-Cholesterol        ≥ 60 mg/dl

    Triglycerides        < 150 mg/dl
   Know Your Diabetes, Metabolic Risk

  Fasting          Healthy        Pre-Diabetes
  Diabetes
                                (Metabolic Syndrome)
Blood Glucose   < 110 mg/dl   110-125 mg/dl      ≥ 126 mg/dl


  2 hr GTT      < 140 mg/dl   140-200 mg/dl      > 200 mg/dl

                                                   Typically
 Triglyceride   < 150 mg/dl   > 150 mg/dl
                                                   elevated

                              M < 40 mg/dl
    HDL         ≥ 60 mg/dl                       Typically low
                              F < 50 mg/dl
   The Metabolic Syndrome
Abdominal Obesity
   Men                   > 40 inch waist
   Women                 > 35 inch waist

Triglycerides            ≥ 150 mg/dL
HDL cholesterol
  Men                     < 40 mg/dL
  Women                   < 50 mg/dL
Blood Pressure          ≥ 130/ 85 mm Hg
Fasting Blood Glucose    110-125 mg/dL
Know Your Blood Pressure

                        Systolic             Diastolic
   Category
                       (mm/Hg)               (mm/Hg)

    Normal            120 or less           80 or less

  High Normal           130-139                85-89

   High Blood
                     140 or more            90 or more
    Pressure
     Strive for blood pressure of 120/80 or less

				
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