Outer surface

Protein A: activates LCAT

Protein B: receptor interactions

Protein C: activates LPL

Protein D: cholesterol ester transfer

Protein E: receptor interactions

Phospolipids, Fatty acids, free cholesterol

Inner core of cholesterol esters and triglycerides

Chylomicrons (CM)

AI, AIV, B48, CI/II/III; E (CM)

Lipids: 90% TG

VLDL

B100, CI/II/III; E

60% TG, 28% chol

LDL

B100

4-8% TG, 50% cholesterol

HDL

AI/II; CI/II/III; E

2-7% TG, 20% cholesterol

• made in parencymal tissues
• requires presence of insulin for synthesis
• Hydrolyzes TG on CM and VLDL to FFAs and glycerol, thus releasing them into circulation
• ApoC accelerates enzyme activity 20x
• bound to endothelial cells in capillaries

LDL-R family has 5 members that are expressed w/ a broad tissue distribution, especially in liver

• High affinity, low capacity pathway; saturated easily

• LDL is degraded in lysosome releasing cholesterol
• choloesterol stored in as CE due to ACAT, used for membranes, steroids or bile

CD36 gene family

• macrophages express these on their membrane
• they are NOT downregulated by high cholesterol levels

• binds bile acids in intestine
• ↓bile returns to liver, liver must use cholesterol to make more bile
• ↑catabolism of plasma LDL due to ↑liver LDL receptors

• type IIa primary cholestrolemia
• type IIb multifactorial
• effects apparent in 4-7 days, may take 2-4 weeks for max effect
• significant patient compliance problem

• Effectiveness attenuated by:                       
• reduced inhibition of HMG-CoA         
• increased production of TG and VLDL

• increased hepatic VLDL assembly and secretion
• nausea
• constipation
• diarrhea

• interferes w/ absorption of acidic drugs: digitalis, warfarin, phenobarbital
• interferes w/ fat soluble vits: A,D,E,K
• can avoid by taking other drug/vit 1 hr before or 4 hours after

• Prototype HMG-CoA reductase inhibitor
• blocks production of mevalonate
• decreased intracellular cholesterol
• increased LDL receptors on liver --> inc endocytosis and catabolism of liver

• 1st line agent to treat hypercholesterolemia
• promotes regression of established atherosclerotic plaques
• patients w/ known CVD should be on a statin
• want <100 cholesterol

1. hepatotoxicity - liver fxn tests done every 6-18 wks during first year, twice a year after
2. Myopathy - very rare
3. use w/ niacin or gmfibrozil ↑risk of myopathy
4. TERATOGEN

HMG-CoA Reductase inhibitor

single daily dose

competitive inhibitor of HMG-CoA reductase

inhibits hepatic synthesis of VLDL

Dual mechanism: block chol synth and hepatic VLDL

Single day dosage

Strong reduction in LDL but not much inc in HDL

• interferes w/ cholesterol absorption from gut
• rapidly absorbed and secreted in bile; low plasma levels
• associates w/ apical membrane of enterocyte
• reduces plasma LDL, additive effect w/ statins
• treat hypercholesterolemia, phytosterolemia

1. inhibits lipolysis in adipose --> dec FFAs
2. inhibits liver synthesis of TGs

• decreased VLDL
• increased HDL (one of the few!)

Generally beneficial in reducing LDL, most potent increase of HDL

• combine w/ resins for hypercholesterolemia
• 1st line agent for hypertriglyceridemia
• dec VLDL in 1-4 days
• dec LDL in 5-7 days
• Max effect: 3-5 weeks

1. cutaneous flushing and pruritis (hard to tolerate) - prostaglandin mediated, can use aspirin to help but tolerance develops
2. slow release formation - hepatic toxicity, hepatitis-like syndrome

• binds to peroxisomal-proliferation activating receptors (PPAR alpha), nuclear steroid receptor
• increases LPL activity
• used for type III familial dysbetalipoproteinemia who don't respond to gemfibrozil
• SE: gall stones, flu-like, arrhythmias

• activates PPARα, ↑LPL
• increases plasma HDL by 10-15%
• treat hyperTGemia
• additive effect w/ bile-binding resins
• SE: GI, rash, inc LDL-Rs/LCAT

• fish reduce morbidity and mortality from atherosclerosis and ischemic heart disease
• omega-3 fatty acids
• compete w/ arachidonic acid to make its own milder thromboxanes and leukotrienes
• inhibit plasma TG synthesis