4Role of Lipids (Lipoproteins) in Metabolism Triglycerides Major energy source for cellsCholesterol Cell growth, cell division, membranerepair, steroid hormone productionLipids Transport of fat soluble vitamins
6Positive and Negative risk Factors in Atherosclerosis Positive NegativeAge: Males > 45 years Elevated HDL cholesterolFemales > 55 years Low LDL cholesterolFamily history of early CHD Good genesElevated LDL cholesterol (>130 mg/dl) Female gender (estrogen)Diabetes mellitus ExceriseHypertensionObesitySmokingCHD, coronary heart disease
7CM Lipoprotein Nomenclature and Composition VLDL IDL LDL HDL Major apoB apoB apoB apoB apoA-IProteinMajor TG TG CE CE CELipidCM= chylomicron TG=triglycerideVLDL= very low density lipoprotein CE= cholesteryl esterIDL= intermediate density lipoproteinLDL= low density lipoproteinHDL= high density lipoproteinApo = apolipoprotein
8Site of Synthesis of Lipoproteins Nascent-HDLapoA-ILiverVLDLapoB-100apoCsapoEIDLLDLapoB-48CMIntestine
9Major Apolipoproteins and Their Function Apo Lipo Origin FunctionApoA-I HDL Liver, intestine Activate LCAT, Cholesterol efflux via ABCA1 transporterApoB-100 VLDL, Liver, intestine Ligand LDL receptor, TGLDL transport from cellsApo(a) Lp(a) Liver Inhibits thrombolysisApoCII HDL, VLDL Liver Activates lipoprotein lipaseApoE VLDL, IDL Liver, intestine Ligand, LDL receptor, LRP receptorLCAT: lecithin:cholesterol acyltransferaseABCA1: ATP binding cassette protein A1LRP: LDL receptor related protein
10Structure of Lp(a)apoB-100LDLCapo(a)SS5N4KringleC444N
11Apo E Isoforms Apo E3 most common, normal isoform a.a. 112 cys a.a. 158 argApo E2 hypercholesteremia, inadequate clearance of remnantsa.a. 158 cysApo E4 elevated triglyceride; Alzheimers diseasea.a. 112 arg
12Alzheimer’s disease and Lipoproteins Early onset AD, prior to age 60:• mutation in amyloid precursor protein gene, chr 21• unidentified gene, chr 14Late 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
13Key Enzymes in Lipoprotein Metabolism • Lipoprotein lipase (LPL): hydrolysis of triglyceride richparticles• Lecithin:cholesterol acyltransferase (LCAT): participates inremoval of excess cholesterol from peripheral cells
18ABCA1 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.
20Reverse 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.
21Reverse Cholesterol Transport Delivery of peripheral tissue cholesterol to the liver for catabolism Requires HDL, apoA-I and LCATPeripheralCelldiffusionHDLUCUCHDLMacrophage/ Foam cellUCABCA1LCATPLLCATNascentHDLHDLCECECEapoA-ISR-B1UC = unesterified cholesterolCE = esterified cholesterolPL = phospholipidLDLr = LDL receptorTGCELiverVLDLor LDLapoBLDLrBile to gut
22The Scavenger Receptor (SR-A1 receptor)How macrophages deal with oxidized or modified LDLThe 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.
23Modification of LDL LDL Apo B-100 Oxidation: Derivatization: Degradation ofB-100 by reactiveoxygen speciesDerivatization:AldehydesGlucosylationeg. diabetesDerivatizedLDLOxidizedLDL
24The Scavenger Receptor: Clearance of modified LDL by macrophages Macrophage Foam CellLipid dropletsOxidized LDLScavengerreceptor(SR-A1)Fatty streaks
25LDL and Atherosclerosis Fitting the pieces together Elevated LDL: Increased residence time in plasmaIncreased modification/oxidation of LDLMonocyteEndothelialcellsCytokinesoxLDLArterywalloxLDL (stimulates cytokine secretion)CytokinesMacrophageSmooth muscle cellproliferationMacrophage foam cell
26HDL Protective Role Fitting the pieces together MonocyteEndothelialcellsoxLDLHDLArterywallUCHDL + UCABCA1apoA-IPLUCoxLDL = oxidized LDLUC = unesterified cholesterolMacrophage foam cellNascent HDL