Cholesterol Metabolism

Structure of cholesterol

• 3 fursed hex rings and 1 pent ring

• sterol → OH on thrid carbon of A ring

• FA is added to chol in ER → less polor and more hydrophobic - better for travel

Overveiw of cholesterols function

• regulates membrane fluidity as cell membrane component

• precursor of hormones (test and est), bile acid, and vitamin D

• be used for bile synthesis

• main source of cholesterol is through synthesis, not diet

• all nucleated cells can synthesize cholesterol from acetyl CoA through the Mevalonate pathway

  • however, main synthesis organs are the liver, intestine, adrenal cortex, ovaries, testes, and placenta

First stage of cholesterol synthesis

• occurs in cytosol

• 3 acetyl CoAs are condensed to geterate 1 HMG-CoA

• HMG-CoA can be converted into mevalonate acid

  • irreversible and rate limiting step

Cholesterol converted to hormones

• occurs in mitochondira

• makes aldosterone, cortisol, testosterone, and estradiol

Cholesterol → bile acid synthesis

Bile/bile salts released from liver

go into gut/intestine and converted into bile acid

Cholesterol transport pathway

• dietary cholesterol packed into CM (released from intestine)

• Dietary cholesterol and TAG packed into VLDL and released from liver

• LDL is taken into cells through endocytosis and cholesterol is released

• excess cholesterol delivered to HDL

  • reverse cholesterol transport back to liver

  • liver will bake bile or new VLDLs

Regulation of cholesterol in first pathway

• negative feedback control by HMG-CoA reductase in Mevalonate synthesis

• inhibited by high levels of cholesterol (rate limited step)

Control biosynthesis of cholesterol by SREBP

• high levels of cholesterol → blocks SREBP from translocating from ER to Golgi → cholesterol synthesis is inhibited

• Low levels of cholesterol → SREBP is located at the ER by SCAP. SCAP holds SREBP into ER

  • SCAP then releases SREBP, SREBP is transported to golgi via COPII transport system

  • in golgi, 2 proteases cleave SREBP resulting in release of SREBP (active transcription factor)

  • SREBP moves to nucleus and initates transcription of target genes like HMG-CoaAR

Regulation: protosomal degradation of HMG-CoA reductase

• high level of cholesterol

• binding/inhibition of HMG CoA accelerates

• degradation of HMG CoA reductase through proteasome degradation pathway

  • inhibits cholesterol synthesis

Lower cholesterol level through drugs (3)

1. inhibition of cholesterol synthesis statin

   1. competatively inhibits HMG-CoA reductase

2. inhibition of cholesterol absorption

   1. Ezetimbe- inhibitor of NPC1, major regulator of cholesterol absorption → lowering plasma cholesterol level

   2. often used with statin together

3. increase LDL clearance - best

   1. PSCK9 secreted from the kidneys, livier, and intestine

   2. binds to LDLR, results in degradation of LDLR receptor

   3. PCSK-9 inhibitor decreased LDLR degradation results in increased LDLR receptor level, therefore more LDLR bound LDLs are endocytosed by liver cells which reduces plasma level of LDL