Lipoprotein Structure, Function, and Metabolism Lipid Transport Lipoprotein Structure, Function, and Metabolism

Clinical Case 8 y.o. girl Medical history Transplantation successful 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 Lipoproteins Structure figure 19-1 LP core Triglycerides Cholesterol esters LP surface Phospholipids Proteins cholesterol

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 Metabolism figure 19-3 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 binding

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

Plasma Lipoproteins Classes & Functions Low Density Lipoprotein (LDL) Synthesized from IDL Cholesterol transport 78% lipid, 58% cholesterol & CE Apo B-100 Receptor binding

VLDL Metabolism figure 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 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

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 Peak Particle Diameter (nm) LDL Particle Size and Apolipoprotein B Predict Ischemic Heart Disease: Quebec Cardiovascular Study 6.2 (p<0.001) Apo B 2.0 >120 mg/dl LDL Particle Size and Apolipoprotein B Predict Ischemic Heart Disease: Quebec Cardiovascular Study In another analysis from the Quebec Cardiovascular Study, men were stratified by apo B level and LDL particle size. High apo B was associated with CHD, and the presence of both high apo B and small, dense LDL was associated with a marked increase in CHD risk. One interpretation of these findings is that concomitant interventions should be used both to lower apo B, such as with a statin, and to improve LDL particle size, such as with fibrates or high-dose statins. However, another interpretation is that if apo B is reduced to less than 120 mg/dL, LDL particle size no longer has an effect, perhaps because if there are few enough apo B-containing particles, it may not matter how atherogenic these particles are. This is a fairly controversial area, although a number of other epidemiological studies also suggest that this might be true. However, the effects of triglyceride level, for instance, which is strongly correlated to LDL particle size, appear to be considerably more important in people with high LDL/HDL ratio, apo B level, or total cholesterol level, as has been seen in the observational Paris Prospective Study and Prospective Cardiovascular Münster (PROCAM) Study and the interventional Helsinki Heart Study. Reference: Lamarche B, Tchernof A, Moorjani S, Cantin B, Dagenais GR, Lupien PJ, Despres JP. Small, dense low-density lipoprotein particles as a predictor of the risk of ischemic heart disease in men: prospective results from the Quebec Cardiovascular Study. Circulation 1997;95:69-75. 1.0 1.0 <120 mg/dl >25.64 <25.64 LDL Peak Particle Diameter (nm) Lamarche B et al. Circulation 1997;95:69-75.

HDL Metabolism: Functions Apoprotein exchange provides apo C and apo E to/from VLDL and chylomicrons Reverse cholesterol transport

Reverse cholesterol transport figure 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 2 Monday, July 18 Lipid Transport Cholesterol Metabolism Format 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