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Sources of lipoproteins • Chylomicron: Intestine • VLDL: Liver • IDL : VLDL • LDL:VLDL • HDL2:Intestine, liver (chylomicrons and VLDLs) • HDL3:Intestine, liver (chylomicrons and VLDLs)
Apolipoproteins • They can form part of the structure of the lipoprotien, apo B • They are enzyme cofactors, C-II for lipoprotein lipase, A-I for lecithin:cholesterol acyltransferase • They act as ligands for interaction with lipoprotein receptors in tissue, apo B-100 and apo E for the LDL receptors, apo E for the remnant receptor and apo A-I for the HDL receptors
Apoprotein Classifications • apoA-I: Chylomicrons, HDL; major protein of HDL, activates lecithin:cholesterol acyltransferase (LCAT) • apoA-II:Chylomicrons, HDL; primarily in HDL, enhances hepatic lipase activity • apoA-IV: Chylomicrons and HDL; present in triacylglycerol rich lipoproteins • apoB-48: Chylomicrons; exclusively found in chylomicrons, derived from apoB-100 gene by RNA editing in intestinal epithelium; lacks the LDL receptor-binding domain of apoB-100 • apoB-100: VLDL, IDL and LDL; major protein of LDL, binds to LDL receptor; one of the longest known proteins in humans
Apoprotein Classifications • apoC-I: Chylomicrons, VLDL, IDL and HDL; may activate LCAT • apoC-II: Chylomicrons, VLDL, IDL and HDL; activates lipoprotein lipase • apoC-III: Chylomicrons, VLDL, IDL and HDL; inhibits lipoprotein lipase • apoD: HDL; closely associated with LCAT • cholesterol ester transfer protein (CETP): HDL; exclusively associated with HDL, cholesteryl ester transfer • apoE (at least 3 alleles [E2, E3, E4] each of which have multiple isoforms): Chylomicron remnants, VLDL, IDL and HDL; binds to LDL receptor
Apoprotein Classifications • apoH: Chylomicrons; triacylglycerol metabolism • apo(a) at least 19 different alleles: LDL, disulfide bonded to apoB-100, forms a complex with LDL identified as lipoprotein (a); strongly resembles plasminogen; may deliver cholesterol to sites of vascular injury, high risk association with premature coronary artery disease and stroke
Binding of a chylomicron to lipoprotein lipase on the inner surface of a capillary.
Cholesterol • Membrane lipid component • Steroid hormones • Vitamin D • Bile acids
Biosynthesis of cholesterol • The pathway that synthesizes cholesterol is important because of the diversity of metabolites it produces • Cholesterol, the precursor to all steroids, derives all of its carbon atoms from acetate (acetyl-CoA). • Stage 1: Formation of Mevalonate • Stage 2: Synthesis of Squalene from Mevalonate • Stage 3: Cyclization of Squalene to Lanosterol and Its Conversion to Cholesterol
Hyperlipoproteinemias • Type-I (familial LPL deficiency, familial hyperchylomicronemia): (a) deficiency of LPL; (b) production of abnormal LPL; (c) apoC-II deficiency, slow chylomicron clearance, reduced LDL and HDL levels • Type II (familial hypercholesterolemia): 4 classes of LDL receptor defect, reduced LDL clearance leads to hypercholesterolemia, resulting in athersclerosis and coronary artery disease • Type III (familial dysbetalipoproteinemia): apolipoprotein E deficiency; hepatic remnant clearance impaired due to apoE abnormality; patients only express the apoE2 isoform that interacts poorly with the apoE receptor, causes xanthomas, hypercholesterolemia and athersclerosis in peripheral and coronary arteries due to elevated levels of chylomicrons and VLDLs
Hyperlipoproteinemias • Familial ligand-defective apoB: 2 different mutations: Gln for Arg (amino acid 3500) or Cys for Arg (amino acid 3531); both lead to reduced affinity of LDL for LDL receptor, dramatic increase in LDL levels; no affect on HDL, VLDL or plasma triglyceride levels; significant cause of hypercholesterolemia and premature coronary artery disease • Familial LCAT deficiency: absence of LCAT leads to inability of HDLs to take up cholesterol (reverse cholesterol transport), decreased levels of plasma cholesteryl esters and lysolecithin
Hypolipoproteinemias • Abetalipoproteinemia: no chylomicrons, VLDLs or LDLs due to defect in apoB expression, rare defect; intestine and liver accumulate lipids, malabsorption of fat, retinitis pigmentosa, ataxic neuropathic disease • Familial hypobetalipoproteinemia: at least 20 different apoB gene mutations identified, LDL concentrations 10-20% of normal, VLDL slightly lower, HDL normal, mild or no pathological changes • Familial alpha-lipoprotein deficiency: apoA-I and C-III deficiencies; all of these related syndromes have reduced HDL concentrations, no effect on chylomicron or VLDL production, tendency to hypertriacylglycerolemia; some elevation in VLDLs