Role of Lipids (Lipoproteins) in Metabolism TriglyceridesMajor energy source for cells CholesterolCell growth, cell division, membrane repair, steroid hormone production LipidsTransport of fat soluble vitamins
Positive and Negative risk Factors in Atherosclerosis PositiveNegative Age: Males > 45 yearsElevated HDL cholesterol Females > 55 yearsLow LDL cholesterol Family history of early CHDGood genes Elevated LDL cholesterol (>130 mg/dl)Female gender (estrogen) Diabetes mellitusExcerise Hypertension Obesity Smoking CHD, coronary heart disease
CM VLDL IDL LDL HDL Lipoprotein Nomenclature and Composition Major apoB apoB apoB apoB apoA-I Protein Major TGTG CE CE CE Lipid CM= chylomicronTG=triglyceride VLDL= very low density lipoproteinCE= cholesteryl ester IDL= intermediate density lipoprotein LDL= low density lipoprotein HDL= high density lipoprotein Apo = apolipoprotein
Nascent-HDL apoA-I Liver VLDL apoB-100 apoCs apoE IDL LDL apoB-100 apoE apoB-100 apoB-48 CM apoCs Intestine Nascent-HDL apoA-I Site of Synthesis of Lipoproteins
Major Apolipoproteins and Their Function ApoLipo OriginFunction ApoA-IHDL Liver, intestineActivate LCAT, Cholesterol efflux via ABCA1 transporter ApoB-100VLDL, Liver, intestineLigand LDL receptor, TG LDLtransport from cells Apo(a)Lp(a) LiverInhibits thrombolysis ApoCIIHDL, VLDL LiverActivates lipoprotein lipase ApoEVLDL, IDL Liver, intestineLigand, LDL receptor, LRP receptor LCAT: lecithin:cholesterol acyltransferase ABCA1: ATP binding cassette protein A1 LRP: LDL receptor related protein
Structure of Lp(a) LDL N C S S C apo(a) apoB-100 4 4 4 4 5 Kringle N
Apo E Isoforms Apo E3 most common, normal isoform a.a. 112 cys a.a. 158 arg Apo E2hypercholesteremia, inadequate clearance of remnants a.a. 112 cys a.a. 158 cys Apo E4elevated triglyceride; Alzheimers disease a.a. 112 arg a.a. 158 arg
Alzheimer’s disease and Lipoproteins Early onset AD, prior to age 60: mutation in amyloid precursor protein gene, chr 21 unidentified gene, chr 14 Late onset AD involves chr 19: apo E gene on chr 19 association of AD with apo E4 allele 80% of familial AD have at least one apo E4 allele apo E4 a major risk factor in AD
Key Enzymes in Lipoprotein Metabolism Lipoprotein lipase (LPL): hydrolysis of triglyceride rich particles Lecithin:cholesterol acyltransferase (LCAT): participates in removal of excess cholesterol from peripheral cells
Lipoprotein Lipase (LPL) LPL Excess Surface Material HDL assembly Fatty Acids and Glycerol Energy apoC-II CM VLDL apoE apoA-I cholesterol phospholipid Endothelial Cell CM VLDL apoE Liver Lipolytic products Bile acids muscle “Remnant” TG TG = triglyceride LDL
LCAT Phospholipid plus cholesterol Nascent HDL LCAT: Disk to sphere transformation Mature HDL Cholesteryl ester (CE) plus lysophospholipid apoA-I CE Cholesteryl ester (CE) Cholesterol Phospholipid ApoA-I Lecithin:Cholesterol Acyl Transferase (LCAT) Free cholesterol Cholesteryl ester
Key Receptors in Lipoprotein Metabolism LDL receptor: catabolism of LDL, apoB ligand ABCA1 transporter: transports excess cholesterol from cells, apoA-I ligand Scavenger receptor A1 (SR-A1): uptake of oxidized and modified LDL by macrophages SR-B1 receptor:selective uptake of excess cholesterol from HDL, apoA-I ligand
ABCA1 Transporter/Receptor Large plasma membrane spanning ATP dependent protein. Essential for moving excess intracellular cholesterol and phospholipid to the plasma membrane. Acts as a flipase, flipping cholesterol and phospholipid from inner leaflet of plasma membrane to outer leaflet. Necessary for removing excess cholesterol from foam cells and preventing early steps in atherosclerosis. ApoA-I is required for capturing the cholesterol released from the foam cell.
Reverse Cholesterol Transport (RCT) The process whereby excess cholesterol in peripheral cells, especially foam cells, is returned to the liver for degradation and excretion. RCT involves apoA-I, ABCA1 and LCAT as well as receptors on the liver for uptake of the excess cholesterol.
Reverse Cholesterol Transport Delivery of peripheral tissue cholesterol to the liver for catabolism Requires HDL, apoA-I and LCAT Peripheral Cell UCHDL CE HDL UC ABCA1 Liver VLDL or LDL apoBLDLr SR-B1 UC PL CE TG diffusion LCAT CE apoA-I UC = unesterified cholesterol CE = esterified cholesterol PL = phospholipid LDLr = LDL receptor Nascent HDL Bile to gut Macrophage/ Foam cell
The Scavenger Receptor (SR-A1 receptor) How macrophages deal with oxidized or modified LDL The scavenger receptor recognizes modified and/or oxidized LDL and internalizes the modified LDL. Accumulation of these modified LDL in the cell leads to the accumulation of cholesterol droplets in the macrophage and the formation of foam cells.
Modification of LDL LDL Apo B-100 Derivatization: Aldehydes Glucosylation eg. diabetes Oxidation: Degradation of B-100 by reactive oxygen species Derivatized LDL Oxidized LDL
The Scavenger Receptor: Clearance of modified LDL by macrophages Oxidized LDL Scavenger receptor MacrophageMacrophage Foam Cell Fatty streaks Lipid droplets (SR-A1)
LDL and Atherosclerosis Fitting the pieces together Elevated LDL: Increased residence time in plasma Increased modification/oxidation of LDL Artery wall Monocyte Endothelial cells oxLDL oxLDL (stimulates cytokine secretion) Macrophage Macrophage foam cell Cytokines Smooth muscle cell proliferation