M.Prasad Naidu MSc Medical Biochemistry, Ph.D.

Research Scholar

Cholesterol Metabolism
Sources of cholesterol
Cholesterol synthesis Long and short term regulation SREBP-2 Lowering cholesterol Calculating your risk for CHD

Roles of Cholesterol
Membrane component
Steroid synthesis Bile acid/salt precursor Vitamin D precursor

Sources of Cholesterol
Diet De novo synthesis Liver cholesterol pool

Cholesterol synthesized in extrahepatic tissues

Secretion of HDL and VLDL

Free cholesterol In bile

Conversion to bile salts/acids

Cholesterol Structure

FA for esterification

Dietary Cholesterol
Animal products eggs
Absorb about 50% Increase intake = decreased absorption Excrete 1 g/day (bile acids)

Dietary Cholesterol
Assume 400 mg intake / day
200 mg is absorbed 1000 mg is excreted 800 mg from de novo synthesis

Lowering cholesterol in diet has very little effect on blood cholesterol !!!

Cholesterol Synthesis
Similar to ketogenic pathway
Occurs in cytosol Requires NADPH and ATP Highly regulated 80 % in liver, ~10% intestine, ~5% skin

CHOLESTEROL SYNTHESIS

HMG CoA Reductase : Regulation

Short-term regulation Inhibited by phosphorylation

AMP-dependent protein kinase When AMP is high (or ATP low!), why waste energy on cholesterol synthesis

Long-term regulation Proteolysis Degradation stimulated by cholesterol and cholesterol metabolites Sterol-sensing domain

HMG CoA reductase Phosphorylation

HMG CoA reductase OH (active) HMG CoA reductase P (inactive)

AMP-Activated Protein Kinase (high activity) (+) phosphatase (+) insulin AMP-Activated Protein Kinase (low activity) AMP kinase (+) increase cAMP Glucagon/epi

HMG CoA Reductase : Regulation

Transcriptional regulation SREBP-2 Responds to cellular levels of sterols

SREBP cleavage activating protein

Site 1 and site 2 protease -

LP

LDL receptor

Negative Feedback (-)

synthesis

Negative Feedback (-)

Free Cholesterol Pool

acat Steroid synthesis C HDL CE

Lowering Cholesterol
Statins decrease HMG CoA

reductase activity Muscle weakness Why?

Lowering Cholesterol
Bile sequestering agents
liver
NH3+ NH3+

Bile acids 95 % reabsorbed

Bile acids

1. Bind bile acid 2. Utilize more cholesterol to make bile acids

>10% 5% in in feces feces

Lowering Cholesterol
Oat bran Soluble fiber Bind bile acids? Niacin 3-8 grams / day (need 60 mg) Inhibits VLDL excretion ? (fatty liver) Flushing and liver damage