Lipid Transport
Lipoprotein Structure, Function, and Metabolism
Clinical Case 8 y.o. girl
Admitted for heart/lung transplantation Medical history
Xanthomas at 2 yo MI symptoms at 7 yo
TC=1240mg/dl TG=350mg/dl Diet & statin & cholestyramine Mother TC= 355, father TC=310
Coronary artery bypass at 7 yo 8 yo severe angina, second bypass
TC = 1000mg/dl Transplantation successful
TC=260mg/dl, xanthomas regressing
Plasma LipoproteinsStructurefigure 19-1
LP core Triglycerides Cholesterol
esters LP surface
Phospholipids Proteins cholesterol
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
Chylomicron Metabolismfigure 19-3
Nascent chylomicron (B-48)
Mature chylomicron (+apo C & apo E)
Lipoprotein lipase Chylomicron
remnant Apo C removed Removed in liver
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
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
Plasma LipoproteinsClasses & Functions
Low Density Lipoprotein (LDL) Synthesized from IDL Cholesterol transport 78% lipid, 58%
cholesterol & CE Apo B-100
Receptor binding
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
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
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.
0
1
2
3
4
5
6
LDL Particle Size and Apolipoprotein B Predict Ischemic Heart Disease: Quebec Cardiovascular
Study
Lamarche B et al. Circulation 1997;95:69-75.
>25.64 <25.64LDL Peak Particle Diameter
(nm)
1.01.0
6.2
(p<0.001)
Apo B
>120 mg/dl
2.0
<120 mg/dl
HDL Metabolism: Functions Apoprotein exchange
provides apo C and apo E to/from VLDL and chylomicrons
Reverse cholesterol transport
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
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
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