Lipid Transport

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Lipid Transport

• Lipoprotein Structure, Function, and Metabolism

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Clinical Case

• 8 y.o. girl
• Admitted for heart/lung transplantation
• Medical history
• Xanthomas at 2 yo
• MI symptoms at 7 yo
• TC1240mg/dl
• TG350mg/dl
• Diet statin cholestyramine
• Mother TC 355, father TC310
• Coronary artery bypass at 7 yo
• 8 yo severe angina, second bypass
• TC 1000mg/dl
• Transplantation successful
• TC260mg/dl, xanthomas regressing

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Plasma LipoproteinsStructurefigure 19-1

• LP core
• Triglycerides
• Cholesterol esters
• LP surface
• Phospholipids
• Proteins
• cholesterol

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Plasma LipoproteinsClasses 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

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Chylomicron Metabolismfigure 19-3

• Nascent chylomicron (B-48)
• Mature chylomicron (apo C apo E)
• Lipoprotein lipase
• Chylomicron remnant
• Apo C removed
• Removed in liver

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Plasma LipoproteinsClasses 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 binding

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Plasma LipoproteinsClasses 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

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Plasma LipoproteinsClasses Functions

• Low Density Lipoprotein (LDL)
• Synthesized from IDL
• Cholesterol transport
• 78 lipid, 58 cholesterol CE
• Apo B-100
• Receptor binding

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VLDL Metabolismfigure 19-4

• 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

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Plasma LipoproteinsClasses 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

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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

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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 CoAcholesterol acyl
  transferase (ACAT)
• increased cholesterol storage
• TG C -gt DG CE
• decreased synthesis of LDL-receptors
• down-regulation
• decreased LDL uptake

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Heterogeneity of LDL-particles

• Not all LDL-particles the same
• Small dense LDL (diameter lt256A)
• Large buoyant LDL (diameter gt256 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 200117859-65.
• 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.

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LDL Particle Size and Apolipoprotein B Predict
Ischemic Heart Disease Quebec Cardiovascular
Study
6.2
(plt0.001)
Apo B
2.0
gt120 mg/dl
1.0
1.0
lt120 mg/dl
gt25.64
lt25.64
LDL Peak Particle Diameter (nm)
Lamarche B et al. Circulation 19979569-75.
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HDL Metabolism Functions

• Apoprotein exchange
• provides apo C and apo E to/from VLDL and
  chylomicrons
• Reverse cholesterol transport

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Reverse cholesterol transportfigure 19-6

• 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

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Resolution of Clinical Case

• Familial hypercholesterolemia (FH)
• Family history
• Early xanthomas and very high TC
• Absence of LDL-receptors
• Homozygous FH
• Parent TC consistent with heterozygous FH
• 1/500 Americans with heterozygous FH, treatable
  with diet/drugs
• 1/106 with homozygous FH
• Diet and drugs relatively ineffective
• Liver has 70 of LDL-receptors
• Combined liver/heart recommended because of
  advance CHD

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Exam 2Monday, July 18

• Lipid Transport
• Chapter 19
• MAAG chapter 54
• Type 2 Diabetes and Insulin Resistance in Adipose
• Effect on LPL causing hyperlipidemia
• Signaling fault resulting in inappropriate
  lipolysis
• Cholesterol Metabolism
• Chapter 21
• MAAG chapter 32
• Format
• Multiple choice questions
• Short essay questions