Atherosclerosis
• Focal plaques within the intima containing cholesterol
and cholesterol esters (CE)
• Affects large and medium sized arteries
• Causes coronary heart diseases (CHD)
• Hypercholesterolemia – high serum cholesterol level
Elevated LDL and triglycerides –
associated with increase risk
Serum HDL levels – inversely related to risk
Pathogenesis
• Chronic inflammatory response of the vascular
wall to endothelial injury or dysfunction
• Elevated plasma LDL levels causing the deposit
of LDL in the subendothelium of blood vessels
• Oxidation of transmigrated LDL
• Activation of endothelial cells
• Recruitment of monocytes/macrophages which
ingest oxLDL through scavenger receptors
• Formation of foam cells – fatty streaks
• Proliferation of smooth muscle cells
• Deposition of extracellular matrix proteins
Monocyte Recruitment
lumen
intima
LDL
Formation of Atherosclerotic Plaques
lumen
neointima
Lipid Core
Plaque Rupture and Thrombosis
Tissue Factor
Platelet Aggregation
Lipid Core
Cholesterol and Triglyceride Metabolism
Exogenous Pathway
• Route of uptake of dietary lipids.
• Chylomicrons (CM) –
complexes of TG, CE and apoproteins
• Chylomicron remnants –
CM after removal of most TG
• CM are degraded by lipoprotein lipase on endothelial
cells of adipose tissue and muscle. After removal of TG
for storage, CM remnants are transported to the liver.
• Results: Dietary TG is stored in adipose tissue and
muscle. Cholesterol is stored in liver or excreted into the
bile as cholesterol or bile acid.
Cholesterol and Triglyceride Metabolism
Endogenous Pathway
• Route for distribution of CE from liver to target cells
• VLDL – secreted by the liver to plasma and transported
to adipose tissue and muscle where lipoprotein lipase
extracted TG. The remnant IDL is either taken up by the
liver or circulates until the remaining TG is removed,
forming LDL particles which are rich in cholesterol.
• LDL is cleared from plasma by LDL receptor-mediated
endocytosis.
• Results: 1) Transfer of TG from liver to target cells via
VLDL; 2) Transfer of CE from liver to target cells via LDL;
3) Feedback regulation of cholesterol homeostasis by
LDL receptor expression; 4) Creation of a steady state
LDL-CE reserve in plasma.
Cholesterol and Triglyceride Metabolism
Reverse Transport of Cholesterol
• Route for cholesterol recovery
• As cell dies and the cell membrane turnover, free
cholesterol is released into the plasma. It is immediately
absorbed onto HDL particles, esterified with a long chain
fatty acid by lecithin:cholesterol acyltransferase (LCAT),
and transferred to VLDL or IDL by a cholesteryl ester
transfer protein (CETP) in plasma. Eventually, it is taken
up by the liver as IDL or LDL.
• Results: Recovery of cholesterol from cell membranes
and reincorporation into LDL pool or return to liver.
Cholesterol and Triglyceride Metabolism
De Novo Cholesterol Biosynthesis
• Liver synthesizes 2/3 of cholesterol made by the body.
The rate limiting enzyme is 3-hydroxyl 3-methyl glutaryl
(HMG)-CoA reductase.
• Results: Provide feedback regulation by cholesterol
concentrations in cells.
Cholesterol Excretion by
Enterohepatic Circulation
• Bile acids are synthesized from cholesterol in the liver,
released into the intestine and reabsorbed in the jejunum
and ileum.
• Results: Conversion of liver cholesterol to bile acids for
recycle.
Genetic Defects of Lipid Metabolism
• Monogenic
Familial hypercholesterolemia
(homozygous or heterozygous)
defect: inactive LDL receptor
Familial lipoprotein lipase deficiency
defect: inactive lipoprotein lipase
Familial combined hyperlipidemia
defect: unknown
• Polygenic/multifactorial – commonly encountered
Hypercholesterolemia
Hypertriglyceridemia
Therapeutic Strategy
A. Identify patients at risk
1. Routine screening of serum cholesterol
2. Assessment of contributing risk factors
B. Non-pharmacologic therapy
1. Diet modification
2. Lifestyle modification
C. Pharmacologic therapy
Classification of
Plasma Cholesterol Concentrations
Total cholesterol
(mg/dl)
< 200
Classification
200 - 239
Borderline
> 240
Desirable
High
Lovastatin aka “statins”
(HMG-CoA reductase inhibitors)
• Action: competitively inhibits HMG-CoA reductase, the
key enzyme for de novo cholesterol biosynthesis.
• Results: 1) cells express more LDL receptors; 2)
decreased serum LDL levels; 3) suppresses production
of VLDL in liver; 4) increased HDL levels; 5) increased
HDL/LDL ratio.
• Advantages: specific; effective; well-tolerated.
• Disadvantages: hepatotoxicity; myopathy; most
expensive; contradicted in pregnant and nursing women.
Bile acid sequestrants
(colestipol, cholestyramine, colesevelam)
• Taken orally, not absorbed from the intestine.
• Action: Anion exchange resins which bind negatively
charged bile acids in the small intestine.
• Results: 1) increased conversion of cholesterol to bile
acid in hepatocytes; 2) increased synthesis of
cholesterol and LDL receptors in hepatocytes; 3)
decreased serum LDL and cholesterol levels.
• Advantages: clinically safe; effective.
• Disadvantages: unpleasant GI effects; interference with
GI drug absorption (e.g., coumarin); may exacerbate
hypertriglyceridemia (unknown mechanism).
Ezetimibe
• Action: inhibits dietary cholesterol uptake by jejunal
enterocytes by binding to a key mediator of cholesterol
absorption – Neimann-Pick C1-Like1 (NPC1L1).
• Results: 1) reduction of cholesterol incorporation into
chylomicrons and delivery to hepatocytes; 2) increased
synthesis of cholesterol and LDL receptors in hepatocytes;
3) decreased serum LDL and cholesterol levels.
• Advantages: clinically safe; effective; used as
monotherapy in statin-intolerant patients; also used in
combination with statins in statin-tolerant patients for
further reduction of serum LDL and cholesterol.
• Disadvantages: no effect on TG absorption; a new class of
anti-atherosclerotic drug – long term effect not known.
Niacin (nicotinic acid)
• Action: Acts through a Gi-coupled GPCR to decrease
cAMP levels. Inhibits hormone-sensitive lipase involved in
lipolysis in adipose tissue and decreases free fatty acid
(FFA) transfer to the liver for synthesis of triglycerides.
• Results: 1) decreased production and release of VLDL by
liver; 2) decreased serum levels of VLDL as well as LDL
and TG; 3) reduced clearance of HDL or increased serum
level of HDL; 4) increased HDL/LDL ratio.
• Advantages: long clinical experience; effective; least
expensive.
• Disadvantages: evokes flushing, itchiness, dyspepsia and
GI discomfort, contraindicated for diabetic patients and
pregnant women; adverse effects in hepatic diseases and
reactivation of gout.
Fibrates (prototype: clofibrate
US: gemfibrozil; Europe: fenofibrate)
• Action: acts through peroxisome proliferator activated
receptors (PPARs) to stimulate gene transcription of
lipoprotein lipase; increases the clearance of VLDL and
reduce plasma TG levels; decreases VLDL synthesis and
lowers LDL levels moderately; increases plasma HDL by
increased synthesis and/or decreased clearance.
• Results: decreased serum TG and cholesterol; increased
HDL/LDL ratio.
• Advantages: recent clinical data support safety and
efficacy; well-tolerated, potential anti-thrombotic effect.
• Disadvantages: more effective in reducing TG than LDL;
increased LDL levels in some patients; displaces
anticoagulant from albumin; contraindicated in patients
with renal failure. Clofibrate has toxic effect.
CETP Inhibitors (Torcetrapib)
• Action: Inhibits the transfer of cholesterol ester from HDL
to VLDL.
• Results: 1) increased serum level of HDL; 2) by itself, no
effect on LDL levels; 3) use in combination of statins to
lower LDL with further increase in HDL.
Combined Drug Therapy
• Advantages: Synergistic approaches utilizes
complementary mechanisms of drug actions; reduces
effective doses of single drug to prevent side effects.
• Hypercholesterol without hypertriglycerides:
Bile acid sequestrant plus lovastatin
Ezetimibe plus lovastatin
Bile acid sequestrant plus lovastatin plus ezetimibe
Bile acid sequestrant plus nicotinic acid
Bile acid sequestrant plus gemfibrozil (less common)
• Hypercholesterol with hypertriglycerides:
Nicotinic acid plus lovastatin
Lovastatin plus gemfibrozil
Nicotinic acid plus lovastatin plus bile acid sequestrant
Probucol
(lipophilic antioxidant)
• Action: Taken up by LDL particles and endothelial cells.
Inhibits oxidation of LDL and prevents ingestion by
macrophage foam cells. Decreases HDL production.
• Results: 1) decreases atherosclerotic plaque formation;
2) small reduction in serum LDL-cholesterol; 3) greater
reduction of serum HDL-cholesterol.
• Advantages: may be used in combination therapy with
other drugs that lower serum LDL-cholesterol.
• Disadvantages: not effective in single drug therapy; no
long term clinical data.