Low Density Lipoprotein (LDL)Low Density Lipoprotein (LDL)

• LDL derived from VLDL as TAG in VLDL (and IDL) removed by lipoprotein lipase

LDL major cholesterol-carrying lipoprotein (levels LDL major cholesterol-carrying lipoprotein (levels correlate more strongly with CHD than total serum correlate more strongly with CHD than total serum cholesterol levels)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 receptorspecific for

apo B-100 foundon IDL and LDL

(ACAT)

Cholesterol:1. added to cell membranes2. represses the synthesis of HMG-CoA Reductase3. stimulates storage of CHL as CHL esters (ACAT = Acyl-CoA:Cholesterol acyltransferase4. represses synthesis of LDL receptors

High Density Lipoprotein (HDL) 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 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 Genetic Diseases of

Lipoprotein MetabolismLipoprotein Metabolism

Diseases of Lipoprotein Metabolism CauseDiseases of Lipoprotein Metabolism Causeby Single Gene Defectsby Single Gene Defects

DiseaseDiseaseFamilial hypercholesterolemia (IIa) (1:500)Familial hypercholesterolemia (IIa) (1:500)

Lipoproteinabnormality Elevated LDL

Lipidabnomality Elevated cholesterol

Metabolic basis Decreased LDL clearance from plasma. Familial form

due to genetic defect in LDL receptor

Clinicalimplications Risk factor (+++) for CHD

Type IIa: Familial hypercholesterolemiaType IIa: Familial hypercholesterolemia

Diseases of Lipoprotein Metabolism CauseDiseases of Lipoprotein Metabolism Causeby Single Gene Defectsby Single Gene Defects

DiseaseDiseaseFamilial combined hyperlipidemia (IIb) (1:100)Familial combined hyperlipidemia (IIb) (1:100)

Lipoproteinabnormality Elevated VLDL & LDL

Lipidabnomality Elevated cholesterol & TAG

Metabolic basis Uncertain; overproduction of apo-B 100?

Clinicalimplications Risk factor (++) for CHD

Diseases of Lipoprotein Metabolism CauseDiseases of Lipoprotein Metabolism Causeby Single Gene Defectsby Single Gene Defects

DiseaseDiseaseFamilial dysbetalipoproteinemia (III) (1:5000)Familial dysbetalipoproteinemia (III) (1:5000)

Lipoproteinabnormality Elevated -VLDL & IDL

Lipidabnomality Elevated cholesterol & TAG

Metabolic basis Decreased LDL clearance of remnants; defective

binding of apo-E to LDL Clinical

implications Risk factor (+) for CHD

Diseases of Lipoprotein Metabolism CauseDiseases of Lipoprotein Metabolism Causeby Single Gene Defectsby Single Gene Defects

DiseaseDiseaseFamilial hypertriglyceridemia (IV) (1:100)Familial hypertriglyceridemia (IV) (1:100)

Lipoproteinabnormality Elevated VLDL

Lipidabnomality Elevated TAG

Metabolic basis Uncertain; VLDL over-production or decreased

catabolism?Clinical

implications Now considered independent Risk factor for CHD

Low Density Lipoprotein (LDL)Low Density Lipoprotein (LDL)

• LDL derived from VLDL as TAG in VLDL (and IDL) removed by lipoprotein lipase

LDL major cholesterol-carrying lipoprotein (levels LDL major cholesterol-carrying lipoprotein (levels correlate more strongly with CHD than total serum correlate more strongly with CHD than total serum cholesterol levels)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 receptorspecific for

apo B-100 foundon IDL and LDL

(ACAT)

Cholesterol:1. added to cell membranes2. represses the synthesis of HMG-CoA Reductase3. stimulates storage of CHL as CHL esters (ACAT = Acyl-CoA:Cholesterol acyltransferase4. represses synthesis of LDL receptors

High Density Lipoprotein (HDL) 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 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 Genetic Diseases of

Lipoprotein MetabolismLipoprotein Metabolism

Diseases of Lipoprotein Metabolism CauseDiseases of Lipoprotein Metabolism Causeby Single Gene Defectsby Single Gene Defects

DiseaseDiseaseFamilial hypercholesterolemia (IIa) (1:500)Familial hypercholesterolemia (IIa) (1:500)

Lipoproteinabnormality Elevated LDL

Lipidabnomality Elevated cholesterol

Metabolic basis Decreased LDL clearance from plasma. Familial form

due to genetic defect in LDL receptor

Clinicalimplications Risk factor (+++) for CHD

Type IIa: Familial hypercholesterolemiaType IIa: Familial hypercholesterolemia

Diseases of Lipoprotein Metabolism CauseDiseases of Lipoprotein Metabolism Causeby Single Gene Defectsby Single Gene Defects

DiseaseDiseaseFamilial combined hyperlipidemia (IIb) (1:100)Familial combined hyperlipidemia (IIb) (1:100)

Lipoproteinabnormality Elevated VLDL & LDL

Lipidabnomality Elevated cholesterol & TAG

Metabolic basis Uncertain; overproduction of apo-B 100?

Clinicalimplications Risk factor (++) for CHD

Diseases of Lipoprotein Metabolism CauseDiseases of Lipoprotein Metabolism Causeby Single Gene Defectsby Single Gene Defects

DiseaseDiseaseFamilial dysbetalipoproteinemia (III) (1:5000)Familial dysbetalipoproteinemia (III) (1:5000)

Lipoproteinabnormality Elevated -VLDL & IDL

Lipidabnomality Elevated cholesterol & TAG

Metabolic basis Decreased LDL clearance of remnants; defective

binding of apo-E to LDL Clinical

implications Risk factor (+) for CHD

Diseases of Lipoprotein Metabolism CauseDiseases of Lipoprotein Metabolism Causeby Single Gene Defectsby Single Gene Defects

DiseaseDiseaseFamilial hypertriglyceridemia (IV) (1:100)Familial hypertriglyceridemia (IV) (1:100)

Lipoproteinabnormality Elevated VLDL

Lipidabnomality Elevated TAG

Metabolic basis Uncertain; VLDL over-production or decreased

catabolism?Clinical

implications Now considered independent Risk factor for CHD

Atherosclerosis – PathogenesisAtherosclerosis – Pathogenesis• Endothelial injury/dysfunctionEndothelial injury/dysfunction

Smoking (hypoxia, carbon monoxide) Hypertension/hemodynamic factors

• Platelet/Monocyte adhesionPlatelet/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 formationPlaque formation Plaque rupture, thrombosis, arterial occlusion, infarction,

death.

Fe2+/Fe3+

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, 20 - 28; 01/06/2005

Nissen, S.E. et al., ibid, 29 - 38

Ehrenstein, M.R., ibid, 73 - 75 (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 NEJM 6/28/01

from NEJM 6/28/01

from NEJM 6/28/01

from Science 4/12/2002From Science 4/12/2002

Atherosclerotic plaque formationAtherosclerotic plaque formation

MEDIA

Fibrous Capsmooth muscle cellsmacrophages, foam cells,lymphocytes, collagenelastin, proteoglycans

Necrotic Centercell debris, cholesterol crystalsfoam cells, calcium

What went wrong with Vioxx™What went wrong with Vioxx™

(and may be a problem with(and may be a problem with

other COX-2 inhibitors) ?other COX-2 inhibitors) ?

Some Properties of Various COX Some Properties of Various COX Inhibitors 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 vascularCOX-2 in vascularendothelial cellsendothelial cells COX-1 in plateletsCOX-1 in platelets

Path in vascularPath in vascularendothelial cellsendothelial cells

Path in plateletsPath in platelets