Cholesterol/Bile

Question 1

Cholesterol structure

Answer 1

4 interlocking rings (6,6,6,5) + hydrocarbon tail
OH group at C3
27C total

Ester in plasma - FA at C3 (super hydrophobic)

Question 2

Cholesterol metabolism

Answer 2

From:
- diet (ester hydrolase -> chylomicrons)
- synthesis in peripheral tissue (-> HDL)
 (inc intestine, adrenal, repoductive, brain)
- synthesis in liver
To:
- VLDL
- bile (both free and acid/salts)

Question 3

Cholesterol synthesis

Answer 3

HMG CoA synthase
3 Ac-CoA -> 3-hydroxy-3-met-glutaryl CoA (HMG CoA)
(cytosolic, also isozyme in mitochondria for ketones)

HMGCoA reductase = RATE LIMITING, irreversible
HMG-CoA + 2 NADPH -> Mevalonic acid + CoA + 2NADP

Mevalonic

• > 5 pyrophosphomevalonate
• > IPP (-> isoprenoids, ubiquinone)
• > DPP (5C) -> GPP (10C)
• > Farnesyl pyrophosphate (FPP, 15C)
• > squalene (30C) -> cyclization (NADPH) ->
• > lanosterol -> -> cholesterol

Question 4

Regulation of cholesterol synthesis

Answer 4

All via HMG-CoA reductase

Transcription:
Low intracellular cholesterol via SREBP (separate slide)
(+) insulin
(-) glucagon

Stability: high chol -> degradation
Allostery: phosphorylated = inactive
(-) AMP -> kinase -> (P) = inactive

Statins inhibit (reversible competitive)

Question 5

Transcriptional regulation of cholesterol

Answer 5

SREBP2:
Normally sequestered in ER
Low chol -> insig (sensor) leaves
->SCAP changes conformation (SREBP chol activating protein) -> S1, S2 proteases -> SREBP released to nucleus
-> transcribes LDL receptor, HMG-CoA reductase

Question 6

Degradation of cholesterol

Answer 6

Ring cannot be metabolized

• > oxysterols (regulatory)
• 24S hydroxy -> excretion from brain
• 27 hydroxy - circulating -> feedback degradation of HMG-CoA reductase
• > steroid hormones (via 450scc -> prenenolone)
• > bile acid -> salt
• > bile free -> modified by bacteria -> coprostanol, cholestanol

Question 7

Bile acids

Answer 7

24 carbons, 2-3 OH, COOH on side chain

Amphipathic -> emulsifier

Question 8

Synthesis of bile acids

Answer 8

Add OH groups
Shorten chain, add COOH
Reduce double bond

Chol-7a-hydroxylase = rate limiting = p450
(-) cholic acid
(+) cholesterol
Overall: chol -> 7alpha -> 25 hydroxy -> acid

Question 9

Bile salts

Answer 9

Bile acid + glycine or taurine (from cysteine)

Side groups negatively charged -> even more amphipathic
Ratio glycine:taurine = 3:1

Intestinal bacteria -> remove -> bile acids -> secondary acids
Reabsorbed -> liver -> reconjugates -> salts -> secretion
(captured by dietary fiber or cholestyramin -> excretion)