Lipid Metabolism 3:Cholesterol biosynthesis, lipoprotein

metabolism, steroid and eicosanoid synthesisBioc 460 Spring 2008 - Lecture 37 (Miesfeld)

Steroids are cholesterol derivatives that have been

used as anabolic enhancers

Mike Brown and Joe Goldstein shared the 1985

Nobel Prize for their work on cholesterol metabolism

Cardiovascular disease is caused by fatty acid deposits that sequester cholesterol in plaques that can break off

• Cholesterol is major component of membranes that is synthesized in liver cells from acetyl-CoA.

• Cholesterol metabolism is an important component of cardiovascular disease because of its association with the formation of atherosclerotic plaques.

• Steroid hormones are cholesterol derivatives that are important physiological ligands and pharmaceutical drugs.

• Eicosanoids are fatty acid derivatives that are precursors to prostaglandins, thromboxanes, and leukotrienes.

Key Concepts in Lipid Metabolism

Cholesterol Biosynthesis

Radioisotope labeling experiments have shown that all 27 carbon atoms of cholesterol are derived from acetyl-CoA.

Stage 1: Generation of mevalonate

from acetyl-CoA

In what turns out to be the rate-limiting step in the cholesterol biosynthetic pathway, the enzyme HMG-CoA reductase converts HMG-CoA to mevalonate in a reduction reaction that uses two molecules of NADPH and releases coenzyme A.

This enzyme is the target of statin drugs.

2 C2

1 C6

Stage 2: Conversion of mevalonate to isopentenyl pyrophosphate and dimethylallyl pyrophosphate

1 C5

1 C5

isomerizeor

1 C6

Stages 3 and 4: formation of cholesterol (C27) from six C5 isoprenoids

1 C5 1 C5

1 C10

+

1 C15

+1 C5

+1 C15

1 C30

1 C27

1 C30

Cholesterol synthesized in the liver has three metabolic fates; stored, exported, or converted to bile acid

What would happen to cholesterol levels in the liver if bile acids were excreted rather than recycled back to the liver?

Bile acid resin

Metabolism of dietary fats and cholesterol

Triacylglycerols and cholesterol are transported through the circulatory system as components of plasma lipoprotein particles that consist of membrane-bound vesicles containing a hydrophobic core and one or more proteins on the surface called apolipoproteins.

Metabolism of dietary fats and cholesterol

Metabolism of dietary fats and cholesterol

Which class of lipoproteins are responsible for the gross blood plasma that appears within 1 hour of eating the triple burger?

Metabolism of dietary fats and cholesterol

"Why is LDL considered "bad cholesterol" and HDL "good cholesterol?"

"Why is LDL considered "bad cholesterol" and HDL "good cholesterol?"

Cardiovascular disease is due to the build-up of cholesterol-rich fibrous plaques in arteries

LDL receptor cycling and cholesterol homeostasis

Statin drugs inhibit cholesterol biosynthesis by blocking the activity of HMG-CoA reductase

1

2

3

4How do statin drugs lower serum LDL levels?

Why would this decrease the risk of cardiovascular disease?

Ezetimibe (Zetia) blocks dietary cholesterol uptake

Ezetimibe (Zetia) blocks dietary cholesterol uptake

Surprisingly, recent clinical studies have shown that Vytorin, a Merck collaborative drug, is no more effective in reducing cardiovascular disease than statin drugs alone.

It is not clear what these new results mean except that serum cholesterol levels alone may not be the best predictor of cardiovascular disease.

Steroid hormones are synthesized from cholesterol

Steroid hormones are synthesized from cholesterol

Eicosanoids Biosynthesis

COX-2 Inhibitors