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

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

(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

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

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

Genetic Diseases of Lipoprotein Metabolism

Diseases of Lipoprotein Metabolism Cause by Single Gene Defects Disease Familial hypercholesterolemia (IIa) (1:500) Lipoprotein abnormalityElevated LDL Lipid abnomalityElevated cholesterol Metabolic basisDecreased LDL clearance from plasma. Familial form due to genetic defect in LDL receptor Clinical implicationsRisk factor (+++) for CHD

Type IIa: Familial hypercholesterolemia

Diseases of Lipoprotein Metabolism Cause by Single Gene Defects Disease Familial combined hyperlipidemia (IIb) (1:100) Lipoprotein abnormalityElevated VLDL & LDL Lipid abnomalityElevated cholesterol & TAG Metabolic basisUncertain; overproduction of apo-B 100? Clinical implicationsRisk factor (++) for CHD

Diseases of Lipoprotein Metabolism Cause by Single Gene Defects Disease Familial dysbetalipoproteinemia (III) (1:5000) Lipoprotein abnormalityElevated  -VLDL & IDL Lipid abnomalityElevated cholesterol & TAG Metabolic basisDecreased LDL clearance of remnants; defective binding of apo-E to LDL Clinical implicationsRisk factor (+) for CHD

Diseases of Lipoprotein Metabolism Cause by Single Gene Defects Disease Familial hypertriglyceridemia (IV) (1:100) Lipoprotein abnormalityElevated VLDL Lipid abnomalityElevated TAG Metabolic basisUncertain; VLDL over- production or decreased catabolism? Clinical implicationsNow considered independent Risk factor for CHD

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

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

(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

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

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

Genetic Diseases of Lipoprotein Metabolism

Diseases of Lipoprotein Metabolism Cause by Single Gene Defects Disease Familial hypercholesterolemia (IIa) (1:500) Lipoprotein abnormalityElevated LDL Lipid abnomalityElevated cholesterol Metabolic basisDecreased LDL clearance from plasma. Familial form due to genetic defect in LDL receptor Clinical implicationsRisk factor (+++) for CHD

Type IIa: Familial hypercholesterolemia

Diseases of Lipoprotein Metabolism Cause by Single Gene Defects Disease Familial combined hyperlipidemia (IIb) (1:100) Lipoprotein abnormalityElevated VLDL & LDL Lipid abnomalityElevated cholesterol & TAG Metabolic basisUncertain; overproduction of apo-B 100? Clinical implicationsRisk factor (++) for CHD

Diseases of Lipoprotein Metabolism Cause by Single Gene Defects Disease Familial dysbetalipoproteinemia (III) (1:5000) Lipoprotein abnormalityElevated  -VLDL & IDL Lipid abnomalityElevated cholesterol & TAG Metabolic basisDecreased LDL clearance of remnants; defective binding of apo-E to LDL Clinical implicationsRisk factor (+) for CHD

Diseases of Lipoprotein Metabolism Cause by Single Gene Defects Disease Familial hypertriglyceridemia (IV) (1:100) Lipoprotein abnormalityElevated VLDL Lipid abnomalityElevated TAG Metabolic basisUncertain; VLDL over- production or decreased catabolism? Clinical implicationsNow considered independent Risk factor for CHD

Atherosclerosis – Pathogenesis Endothelial injury/dysfunction Endothelial injury/dysfunction  Smoking (hypoxia, carbon monoxide)  Hypertension/hemodynamic factors Platelet/Monocyte adhesion 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 formation  Plaque rupture, thrombosis, arterial occlusion, infarction, death.

Fe 2+ /Fe 3+

 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. Med 352:1, ; 01/06/2005Nissen, S.E. et al., ibid, Ehrenstein, M.R., ibid, (editorial)

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 From Science 4/12/2002 CRP = C-reative protein

From Science 4/12/2002

Atherosclerotic plaque formation

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

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

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

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

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