M.Prasad NaiduMSc Medical Biochemistry,

Ph.D.Research Scholar

Cholesterol MetabolismSources of cholesterolCholesterol synthesis

Long and short term regulationSREBP-2Lowering cholesterolCalculating your risk for CHD

Roles of Cholesterol

Membrane component

Steroid synthesis

Bile acid/salt precursor

Vitamin D precursor

Sources of CholesterolDiet De novo synthesis

Cholesterol synthesized in extrahepatic tissues

Liver cholesterolpool

Free cholesterolIn bile

Conversion to bile salts/acidsSecretion of HDLand VLDL

Cholesterol Structure

FA for esterification

Dietary CholesterolAnimal products – eggsAbsorb about 50%Increase intake = decreased absorptionExcrete – 1 g/day (bile acids)

Dietary CholesterolAssume 400 mg intake / day200 mg is absorbed1000 mg is excreted800 mg from de novo synthesis

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

Cholesterol SynthesisSimilar to ketogenic pathway

Occurs in cytosol

Requires NADPH and ATP

Highly regulated

80 % in liver, ~10% intestine, ~5% skin

CHOLESTEROL SYNTHESIS

HMG CoA Reductase : RegulationShort-term regulation

Inhibited by phosphorylation AMP-dependent protein kinase When AMP is high (or ATP low!), why waste energy

on cholesterol synthesisLong-term regulation

ProteolysisDegradation stimulated by cholesterol and

cholesterol metabolitesSterol-sensing domain

HMG CoA reductase - Phosphorylation

AMP-ActivatedProtein Kinase (high activity)

AMP-ActivatedProtein Kinase(low activity)

phosphatase

insulin

(+)

kinase

Glucagon/epi

(+)

increase cAMP

AMP

(+)

HMG CoA reductase – OH (active)

HMG CoA reductase – P (inactive)

HMG CoA Reductase : RegulationTranscriptional regulation

SREBP-2 Responds to cellular levels of sterols

SREBP cleavageactivating protein

Site 1 and site 2 protease -

Free Cholesterol Pool

synthesisNegative Feedback (-)

LDL receptor

LP

NegativeFeedback (-)

acat

CE

HDL

Steroid synthesis

C

Lowering CholesterolStatins – decrease HMG

CoA reductase activityMuscle weaknessWhy?

Lowering CholesterolBile sequestering agents

Bileacids

liver

Bile acids

95 % reabsorbed

5% in feces

NH3+

NH3+

1. Bind bile acid2. Utilize more cholesterol to make bile acids

>10% in feces

Lowering CholesterolOat bran

Soluble fiberBind bile acids?

Niacin 3-8 grams / day (need 60 mg)Inhibits VLDL excretion ? (fatty liver)Flushing and liver damage