LipoproteinsLipoprotein Apoproteins FunctionChylomicron apoB-48, apoC, apoE Transport TGs form intestine to liver/ other tissuesVLDL apoB-100, apoC, apoE Transport TGs from liver to adipose/ muscles.IDL apoB-48, apoC, apoE Intermediary between VLDL and LDLLDL apoB-48 Transport cholesterol to peripheral tissues.HDL apoA, apoC, apoE, •Absorb cholesterol form peripheral tissues apoD and transport it to liver •Reservoir for exchange of lipoproteins in VLDL and Chylomicron metabolism
Apoproteins: o Regulate the metabolism of lipoproteins by modulating the activity of enzymes o Mediate the receptor mediated uptake of lipoproteinsTwo kinds 1. Integral proteins : Name Lipoprotein Function • apoA-I Apo-A Name Lipoprotein Name Lipoprotein Function Function Activates LCAT HDL, Nascent chylomicrons Structural • Apo-B (B-48 &B-100)VLDL, IDL apoC-I apoB-100 HDL, IDL, LDL VLDL, Activator of LCAT Structural Name apoA-II Chylomicrons Lipoprotein SynthesisFunction Structural HDL, Nascent and secretion of VLDL 2. PeripheralapoC-II Chylomicrons Binds to LDL ReceptorLipoprotein proteins: VLDL, IDL chylomicrons to receptor on the apoE HDL, Activator of Binds • Apo- C ApoB-48 HDL, VLDL, IDL Structural membrane of liver Chylomicrons Chylomicrons, lipase (LPL) cell • Apo- E (RNA Chylomicron apoC-III Chylomicrons apoD HDL, SynthesisStabilizes surface exchange and secretion of Cholestreyl ester EDITING) HDL, VLDL, IDL Chylomicrons remnant Chylomicrons nascent
VLDL/ CM Remnant Albumin Phospholipids Cholesterol PLTP LCAT CELL CETP HDL
Statins: Fibric Acids HMG CoA Reductase •ReducesBile Acid inhibitors synthesis of VLDLSeqestrants in liver•Bind and remove •Increasesbile in intestine catabolism of•Increases VLDLcholesterolconversion to bileCholesterolAbsorption InhibitorEzetimibe:•Inhibits transporterprotein on surface ofintestinal absorptivecells.•Blocks uptake ofdietary cholesterolin small intestine.
ABCA1 Transporter/ReceptorLarge plasma membrane spanning ATP dependent protein.Essential for moving excess intracellular cholesterol and phospholipid tothe plasma membrane.Acts as a flipase, flipping cholesterol and phospholipid from innerleaflet of plasma membrane to outer leaflet.Necessary for removing excess cholesterol from foam cells andpreventing early steps in atherosclerosis.ApoA-I is required for capturing the cholesterol released from the foam cell.
The Scavenger Receptor (SR-A1 receptor) How macrophages deal with oxidized or modified LDLThe scavenger receptor recognizes modified and/or oxidizedLDL and internalizes the modified LDL.Accumulation of these modified LDL in the cell leads to theaccumulation of cholesterol droplets in the macrophage and theformation of foam cells.
Modification of LDL LDL Apo B-100Derivatization: Oxidation:Aldehydes Degradation ofGlucosylation B-100 by reactiveeg. diabetes oxygen species Derivatized Oxidized LDL LDL
LDL and Atherosclerosis Fitting the pieces together Elevated LDL: Increased residence time in plasma Increased modification/oxidation of LDL Monocyte Endothelial cells oxLDLArtery oxLDL (stimulates cytokine secretion) wall Macrophage Smooth muscle cell proliferation Macrophage foam cell