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Lipoprotein metabolism, Shariq
- 1. Lipoprotein metabolism Syed Shariq Naeem
- 2. Outline • Introduction – Structure and Function • Apoproteins • Chylomicron Metabolism • VLDL, IDL & LDL Metabolism • HDL & Reverse cholesterol transport • Targets for Treating Dyslipidemia
- 3. Structure of lipoprotein INTEGRAL APOPROTEINS MONOLAYER OF PHOSPHOLIPID AND CHOLESTERLOL CHOLESTEROL CORE ESTERS TRIGLYCERIDES PERIPHERAL APOPROTEINS
- 4. Nomenclature of lipoproteins Diameter Protein Triglycerides Cholestery nm % % l esters % Chylomicron 75-1200 1 88 3 VLDL 30-80 10 56 15 IDL 25-30 10 29 34 LDL 18-25 ~20 13 48 HDL 5-12 ~50 13 30 Albumin Fatty acid complex
- 5. Lipoproteins Lipoprotein Apoproteins Function Chylomicron apoB-48, apoC, apoE Transport TGs form intestine to liver/ other tissues VLDL apoB-100, apoC, apoE Transport TGs from liver to adipose/ muscles. IDL apoB-48, apoC, apoE Intermediary between VLDL and LDL LDL 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
- 6. Apoproteins: oRegulate the metabolism of lipoproteins by modulating the activity of enzymes o Mediate the receptor mediated uptake of lipoproteins Two 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
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- 10. apo B-48 Fat CCK Bile salts Duodenum Chylomicron Micelles ACAT Enterocytes apo-C apo-E Lacteal Thoracic duct Systemic circulation
- 11. LDL-R Chylomicron remnant receptor apo-B-48 VLDL apo-E apo-C Liver Chylomicron apoE Adipocyte Chylomicron remnant When TGs < 20% remaining, they loose apoC
- 12. Endogenous Pathway VLDL Synthesisand Processing Conversion of VLDL to LDL LDL Uptake
- 13. apo-B-100 HDL Liver VLDL apo-B-100 TGs <50% Remains LPL attached to LPL Adipocyte & VLDL VLDL Remnant Cell wall Myocyte LDL-R Aldosterone TGs <30% Cortisol Sex hormones IDL TGs < 10% Loses apoE & apoC LDL apoB-100
- 14. Hepatic uptake ofRemnant Particles CM OR VLDL REMNANT HSPG Sequestration HEPATIC LIPASE Space of Disse Lipolysis Uptake HEPATOCYTE LDL-R LRP LRP-HSPG HSPG
- 15. Reverse Cholesterol Transport– Role of HDL LCAT CETP
- 16. • All cellscan make Cholesterol • Only HDL can pick up cholesterol from Peripheral Tissues • Only the liver can degrade cholesterol
- 17. apoA VLDL REMNANT Liver LCAT Pre-β-HDL SR-B1 ABCA1 apoA α -HDL Hepatic lipase
- 18. VLDL/ CM Remnant Albumin Phospholipids Cholesterol PLTP LCAT CELL CETP HDL
- 19. Statins: Fibric Acids HMG CoA Reductase •Reduces Bile Acid inhibitors synthesis of VLDL Seqestrants in liver •Bind and remove •Increases bile in intestine catabolism of •Increases VLDL cholesterol conversion to bile Cholesterol Absorption Inhibitor Ezetimibe: •Inhibits transporter protein on surface of intestinal absorptive cells. •Blocks uptake of dietary cholesterol in small intestine.
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- 26. ABCA1 Transporter/Receptor Large plasmamembrane 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.
- 27. 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.
- 28. Modification of LDL LDL Apo B-100 Derivatization: Oxidation: Aldehydes Degradation of Glucosylation B-100 by reactive eg. diabetes oxygen species Derivatized Oxidized LDL LDL
- 29. LDL and Atherosclerosis Fitting the pieces together Elevated LDL: Increased residence time in plasma Increased modification/oxidation of LDL Monocyte Endothelial cells oxLDL Artery oxLDL (stimulates cytokine secretion) wall Macrophage Smooth muscle cell proliferation Macrophage foam cell
- 30. HDL Protective Role Fitting the pieces together HDL Monocyte Endothelial cells oxLDL HDL Artery UC wall HDL + UC apoA-I ABCA1 PL UC oxLDL = oxidized LDL Macrophage foam cell UC = unesterified cholesterol Nascent HDL
- 31. apo-B-48 apo-E apo-C apo-B-48 apo-E apo-C
- 32. VLDL LCAT Chylomicron remnant receptor
- 33. LDL DELIVERS CHOLESTEROLTO CELLS LDL LDL Receptors SYNTHESIS OF CHOLESTEROL SYNTHESIS OF HMG CoA LDL RECEPTORS Reductase DNA INHIBITS INHIBITS RNA EXCESS CHOLESTEROL ACAT ACTIVATES MEMBRANES STEROIDS CHOLESTEROL BILE ACIDS ESTERS
- 35. Diameter Protein Triglycerides Cholestery nm % % l esters % Chylomicron 75-1200 1 88 3 VLDL 30-80 10 56 15 IDL 25-30 10 29 34 LDL 18-25 ~20 13 48 HDL 5-12 ~50 13 30
- 36. LDL Receptor (apoB-Ereceptor) Regulates cholesterol synthesis and plasma cholesterol levels HMG-CoA reductase Cholesteryl ester LDL (storage) Receptors LDL-Receptors ACA T Cholesterol LDL LDL Amino Endosome Lysosome acids
Editor's Notes
- #7 RNA editing – C at positon 6666 in converted to T, which makes GAA (glutamine) – TO -- UAA (stop codon) in intestine