cholesterol

1
CHOLESTEROL METABOLISM

• M.Prasad Naidu
• MSc Medical Biochemistry,
• Ph.D.Research Scholar

2
Cholesterol Metabolism

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

3
Roles of Cholesterol

• Membrane component
• Steroid synthesis
• Bile acid/salt precursor
• Vitamin D precursor

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Sources of Cholesterol
Cholesterol synthesized in extrahepatic tissues
De novo synthesis
Diet
Liver cholesterol pool
Free cholesterol In bile
Conversion to bile salts/acids
Secretion of HDL and VLDL
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Cholesterol Structure
FA for esterification
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Dietary Cholesterol

• Animal products eggs
• Absorb about 50
• Increase intake decreased absorption
• Excrete 1 g/day (bile acids)

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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 !!!

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Cholesterol Synthesis

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

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CHOLESTEROL SYNTHESIS
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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

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HMG CoA reductase - Phosphorylation
HMG CoA reductase OH (active)
HMG CoA reductase P (inactive)
AMP-Activated Protein Kinase (high
activity)
()
AMP
phosphatase
kinase
()
()
AMP-Activated Protein Kinase (low activity)
increase cAMP
insulin
Glucagon/epi
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HMG CoA Reductase Regulation

• Transcriptional regulation
• SREBP-2
• Responds to cellular levels of sterols

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SREBP cleavage activating protein
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Site 1 and site 2 protease -
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(No Transcript)
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LP
LDL receptor
Negative Feedback (-)
synthesis
Free Cholesterol Pool
Negative Feedback (-)
acat
Steroid synthesis
CE
C
HDL
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Lowering Cholesterol

• Statins decrease HMG CoA reductase activity
• Muscle weakness
• Why?

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Lowering Cholesterol

• Bile sequestering agents

liver
Bile acids
Bile acids
95 reabsorbed

• Bind bile acid
• Utilize more cholesterol
• to make bile acids

5 in feces
gt10 in feces
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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

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THANK YOU