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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.

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Presentation Transcript
cholesterol metabolism
Cholesterol Metabolism
  • Sources of cholesterol
  • Cholesterol synthesis
    • Long and short term regulation
  • SREBP-2
  • Lowering cholesterol
  • Calculating your risk for CHD
roles of cholesterol
Roles of Cholesterol
  • Membrane component
  • Steroid synthesis
  • Bile acid/salt precursor
  • Vitamin D precursor
sources of cholesterol
Sources of Cholesterol

Cholesterol synthesized

in extrahepatic tissues

De novo synthesis

Diet

Liver cholesterol

pool

Secretion of HDL

and VLDL

Free cholesterol

In bile

Conversion to bile salts/acids

cholesterol structure
Cholesterol Structure

FA for esterification

dietary cholesterol
Dietary Cholesterol
  • Animal products – eggs
  • Absorb about 50%
  • Increase intake = decreased absorption
  • Excrete – 1 g/day (bile acids)
dietary cholesterol6
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
Cholesterol Synthesis

Similar to ketogenic pathway

Occurs in cytosol

Requires NADPH and ATP

Highly regulated

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

hmg coa reductase regulation
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
slide10

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

hmg coa reductase regulation11
HMG CoA Reductase : Regulation
  • Transcriptional regulation
    • SREBP-2
    • Responds to cellular levels of sterols
slide12

SREBP cleavage

activating protein

slide15

LP

LDL

receptor

Negative

Feedback (-)

synthesis

Free Cholesterol Pool

Negative

Feedback (-)

acat

Steroid synthesis

CE

C

HDL

lowering cholesterol
Lowering Cholesterol
  • Statins – decrease HMG CoA reductase activity
    • Muscle weakness
    • Why?
lowering cholesterol17

NH3+

NH3+

Lowering Cholesterol
  • Bile sequestering agents

liver

Bile

acids

Bile acids

95 % reabsorbed

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

>10% in feces

5% in feces

lowering cholesterol18
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