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Lipoprotein metabolism, Shariq

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lipids, lipoprotein metabolism

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Lipoprotein metabolism, Shariq

  1. 1. Lipoprotein metabolism Syed Shariq Naeem
  2. 2. Outline• Introduction – Structure and Function• Apoproteins• Chylomicron Metabolism• VLDL, IDL & LDL Metabolism• HDL & Reverse cholesterol transport• Targets for Treating Dyslipidemia
  3. 3. Structure of lipoprotein INTEGRAL APOPROTEINS MONOLAYER OF PHOSPHOLIPID AND CHOLESTERLOLCHOLESTEROL CORE ESTERSTRIGLYCERIDES PERIPHERAL APOPROTEINS
  4. 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. 5. 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
  6. 6. 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
  7. 7. Cholesterol biosynthesis
  8. 8. Exogenous PathwayChylomicron Processing
  9. 9. apo B-48 Fat CCK Bile salts DuodenumChylomicron Micelles ACAT Enterocytes apo-C apo-E Lacteal Thoracic duct Systemic circulation
  10. 10. LDL-R Chylomicron remnant receptor apo-B-48 VLDL apo-E apo-C LiverChylomicron apoE Adipocyte Chylomicron remnant When TGs < 20% remaining, they loose apoC
  11. 11. Endogenous PathwayVLDL Synthesis and Processing Conversion of VLDL to LDL LDL Uptake
  12. 12. apo-B-100 HDL Liver VLDL apo-B-100 TGs <50%Remains LPLattached toLPL Adipocyte & VLDL VLDL Remnant Cell wall Myocyte LDL-R AldosteroneTGs <30% Cortisol Sex hormones IDLTGs < 10% Loses apoE & apoC LDL apoB-100
  13. 13. Hepatic uptake of Remnant Particles CM OR VLDL REMNANT HSPGSequestration HEPATIC LIPASE Space of DisseLipolysisUptake HEPATOCYTE LDL-R LRP LRP-HSPG HSPG
  14. 14. Reverse Cholesterol Transport – Role of HDL LCAT CETP
  15. 15. • All cells can make Cholesterol• Only HDL can pick up cholesterol from Peripheral Tissues• Only the liver can degrade cholesterol
  16. 16. apoA VLDL REMNANT Liver LCAT Pre-β-HDLSR-B1 ABCA1 apoA α -HDLHepaticlipase
  17. 17. VLDL/ CM Remnant Albumin Phospholipids Cholesterol PLTP LCAT CELL CETP HDL
  18. 18. 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.
  19. 19. Thank you
  20. 20. 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.
  21. 21. 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.
  22. 22. Modification of LDL LDL Apo B-100Derivatization: Oxidation:Aldehydes Degradation ofGlucosylation B-100 by reactiveeg. diabetes oxygen species Derivatized Oxidized LDL LDL
  23. 23. 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
  24. 24. HDL Protective Role Fitting the pieces together HDL Monocyte Endothelial cells oxLDL HDLArtery UCwall HDL + UC apoA-I ABCA1 PL UC oxLDL = oxidized LDL Macrophage foam cell UC = unesterified cholesterol Nascent HDL
  25. 25. apo-B-48 apo-E apo-Capo-B-48 apo-E apo-C
  26. 26. VLDL LCATChylomicron remnant receptor
  27. 27. LDL DELIVERS CHOLESTEROL TO 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
  28. 28. 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
  29. 29. LDL Receptor (apoB-E receptor)Regulates cholesterol synthesis and plasma cholesterol levels HMG-CoA reductase Cholesteryl ester LDL (storage) ReceptorsLDL-Receptors ACA T Cholesterol LDL LDL Amino Endosome Lysosome acids

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