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