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Low Density Lipoprotein (LDL). LDL derived from VLDL as TAG in VLDL (and IDL) removed by lipoprotein lipase LDL major cholesterol-carrying lipoprotein (levels correlate more strongly with CHD than total serum cholesterol levels) LDL taken up by liver via LDL receptor which recognizes apo B100

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Low Density Lipoprotein (LDL)


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    1. Low Density Lipoprotein (LDL) • LDL derived from VLDL as TAG in VLDL (and IDL) removed by lipoprotein lipase • LDL major cholesterol-carrying lipoprotein (levels correlate more strongly with CHD than total serum cholesterol levels) • LDL taken up by liver via LDL receptor which recognizes apo B100 • High levels of LDL, small LDL size and oxidized LDL increase risk of atherosclerosis

    2. LDL receptor specific for apo B-100 found on IDL and LDL

    3. (ACAT) Cholesterol: 1. added to cell membranes 2. represses the synthesis of HMG-CoA Reductase 3. stimulates storage of CHL as CHL esters (ACAT = Acyl-CoA:Cholesterol acyltransferase 4. represses synthesis of LDL receptors

    4. High Density Lipoprotein (HDL) • HDL functions in reverse cholesterol transport – removal of cholesterol from peripheral tissues • Nascent HDL is newly synthesized from apo A-I and phospholipid and accepts cholesterol from cell membranes • LCAT (lecithin-cholesterol acyltransferase) converts HDL cholesterol to cholesterol ester

    5. HDL - continued • CETP (cholesterol ester transfer protein) transfers cholesterol ester from HDL to VLDL remnants in exchange for triacylglycerol • Hepatic lipase degrades HDL • HDL can also be taken up without degradation by HDL receptor • Thus, peripheral cholesterol is transferred to liver either after transfer to LDL or via HDL receptor • Low levels of HDL correlate with increased risk of CHD

    6. Genetic Diseases of Lipoprotein Metabolism

    7. Diseases of Lipoprotein Metabolism Cause by Single Gene Defects Disease Familial hypercholesterolemia (IIa) (1:500) Lipoprotein abnormality Elevated LDL Lipid abnomality Elevated cholesterol Metabolic basis Decreased LDL clearance from plasma. Familial form due to genetic defect in LDL receptor Clinical implications Risk factor (+++) for CHD

    8. Type IIa: Familial hypercholesterolemia

    9. Diseases of Lipoprotein Metabolism Cause by Single Gene Defects Disease Familial combined hyperlipidemia (IIb) (1:100) Lipoprotein abnormality Elevated VLDL & LDL Lipid abnomality Elevated cholesterol & TAG Metabolic basis Uncertain; overproduction of apo-B 100? Clinical implications Risk factor (++) for CHD

    10. Diseases of Lipoprotein Metabolism Cause by Single Gene Defects Disease Familial dysbetalipoproteinemia (III) (1:5000) Lipoprotein abnormality Elevated  -VLDL & IDL Lipid abnomality Elevated cholesterol & TAG Metabolic basis Decreased LDL clearance of remnants; defective binding of apo-E to LDL Clinical implications Risk factor (+) for CHD

    11. Diseases of Lipoprotein Metabolism Cause by Single Gene Defects Disease Familial hypertriglyceridemia (IV) (1:100) Lipoprotein abnormality Elevated VLDL Lipid abnomality Elevated TAG Metabolic basis Uncertain; VLDL over- production or decreased catabolism? Clinical implications Now considered independent Risk factor for CHD

    12. Low Density Lipoprotein (LDL) • LDL derived from VLDL as TAG in VLDL (and IDL) removed by lipoprotein lipase • LDL major cholesterol-carrying lipoprotein (levels correlate more strongly with CHD than total serum cholesterol levels) • LDL taken up by liver via LDL receptor which recognizes apo B100 • High levels of LDL, small LDL size and oxidized LDL increase risk of atherosclerosis

    13. LDL receptor specific for apo B-100 found on IDL and LDL

    14. (ACAT) Cholesterol: 1. added to cell membranes 2. represses the synthesis of HMG-CoA Reductase 3. stimulates storage of CHL as CHL esters (ACAT = Acyl-CoA:Cholesterol acyltransferase 4. represses synthesis of LDL receptors

    15. High Density Lipoprotein (HDL) • HDL functions in reverse cholesterol transport – removal of cholesterol from peripheral tissues • Nascent HDL is newly synthesized from apo A-I and phospholipid and accepts cholesterol from cell membranes • LCAT (lecithin-cholesterol acyltransferase) converts HDL cholesterol to cholesterol ester

    16. HDL - continued • CETP (cholesterol ester transfer protein) transfers cholesterol ester from HDL to VLDL remnants in exchange for triacylglycerol • Hepatic lipase degrades HDL • HDL can also be taken up without degradation by HDL receptor • Thus, peripheral cholesterol is transferred to liver either after transfer to LDL or via HDL receptor • Low levels of HDL correlate with increased risk of CHD

    17. Genetic Diseases of Lipoprotein Metabolism

    18. Diseases of Lipoprotein Metabolism Cause by Single Gene Defects Disease Familial hypercholesterolemia (IIa) (1:500) Lipoprotein abnormality Elevated LDL Lipid abnomality Elevated cholesterol Metabolic basis Decreased LDL clearance from plasma. Familial form due to genetic defect in LDL receptor Clinical implications Risk factor (+++) for CHD

    19. Type IIa: Familial hypercholesterolemia

    20. Diseases of Lipoprotein Metabolism Cause by Single Gene Defects Disease Familial combined hyperlipidemia (IIb) (1:100) Lipoprotein abnormality Elevated VLDL & LDL Lipid abnomality Elevated cholesterol & TAG Metabolic basis Uncertain; overproduction of apo-B 100? Clinical implications Risk factor (++) for CHD

    21. Diseases of Lipoprotein Metabolism Cause by Single Gene Defects Disease Familial dysbetalipoproteinemia (III) (1:5000) Lipoprotein abnormality Elevated  -VLDL & IDL Lipid abnomality Elevated cholesterol & TAG Metabolic basis Decreased LDL clearance of remnants; defective binding of apo-E to LDL Clinical implications Risk factor (+) for CHD

    22. Diseases of Lipoprotein Metabolism Cause by Single Gene Defects Disease Familial hypertriglyceridemia (IV) (1:100) Lipoprotein abnormality Elevated VLDL Lipid abnomality Elevated TAG Metabolic basis Uncertain; VLDL over- production or decreased catabolism? Clinical implications Now considered independent Risk factor for CHD

    23. Atherosclerosis – Pathogenesis • Endothelial injury/dysfunction • Smoking (hypoxia, carbon monoxide) • Hypertension/hemodynamic factors • Platelet/Monocyte adhesion • Release of growth factors, chemo attractants • Smooth muscle proliferation – extracellular matrix production • Macrophage infiltration and lipid uptake (oxidized LDL, ?remnants) – Foam cell formation • Cell death – necrotic center, extracellular lipid accumulation, calcification • Plaque formation • Plaque rupture, thrombosis, arterial occlusion, infarction, death.

    24. Fe2+/Fe3+

    25. Now recognized that atherosclerosis has a significant inflammatory component, and, in parallel, statins appear to inhibit inflammatory processes directly • Recent evidence* that statins not only inhibit cholesterol synthesis, but independently reduce circulating levels of C-reactive protein (CRP), a stable biomarker of inflammation • This has implications for a dual role for statins • Reduces level of LDL cholesterol • Decreases inflammatory component of atherosclerosis *Ricker, P.M. et al., N. Engl. J. Med352:1,20 - 28; 01/06/2005 Nissen, S.E. et al., ibid,29 - 38 Ehrenstein, M.R., ibid,73 - 75 (editorial)

    26. From Science 4/12/2002 CRP = C-reative protein Inflammation is a response to injury or other insult (infection, etc.) For example, the process of building atherosclerotic plaque is injury and the arterial intima becomes inflamed. This can lead to secretion of inflammatory cytokines Other potential triggers of inflammatory response include hypertension, smoking and chronic low-level infections, such as gingivitis and periodontitis

    27. From Science 4/12/2002

    28. Atherosclerotic plaque formation

    29. Fibrous Cap smooth muscle cells macrophages, foam cells, lymphocytes, collagen elastin, proteoglycans Necrotic Center cell debris, cholesterol crystals foam cells, calcium MEDIA

    30. What went wrong with Vioxx™ (and may be a problem with other COX-2 inhibitors) ?

    31. Some Properties of Various COX Inhibitors • Aspirin and other common NSAIDs are analgesic, antipyretic & anti-inflamatory drugs • Aspirin and other common NSAIDs inhibit COX-1 and, to varying extents, COX-2, but NOT COX-3 • Celebrex®, Vioxx®, Lodine®, and Mobic® are selective inhibitors of COX-2; have little, if any effects on COX-1 or COX-3 • COX-2 inhibitors frequently prescribed for arthritis sufferers because of reduced incidence of gastric bleeding with chronic use

    32. Science, 2002 What’s the problem with Vioxx™?

    33. COX-2 in vascular endothelial cells COX-1 in platelets Path in platelets Path in vascular endothelial cells