OIA1003 CHOLESTEROL METABOLISM

Cholesterol

A 27-carbon steroid alcohol found in all animal tissues; essential for membrane structure and as a precursor for bile acids, steroid hormones, and vitamin D.

Sources of cholesterol

Synthesized in most tissues (especially liver, intestine, adrenal cortex, gonads) or obtained from the diet.

Cholesterol transport

Transported in lipoproteins or secreted into bile as cholesterol or bile salts.

Cholesterol elimination

Excreted from liver as free cholesterol or converted into bile acids/salts and secreted into bile.

Building block of cholesterol

All 27 carbon atoms are derived from acetyl-CoA.

Stage 1: Mevalonate synthesis

Acetyl-CoA → HMG-CoA → Mevalonate via HMG-CoA reductase (rate-limiting step).

Stage 2: Isoprenoid unit formation

Mevalonate → Isopentenyl pyrophosphate (IPP), the 5-carbon isoprenoid unit.

Stage 3: Squalene formation

Six isoprenoid units condense to form squalene.

Stage 4: Cyclization

Squalene → Lanosterol (first sterol structure via cyclization).

Stage 5: Cholesterol formation

Lanosterol is modified (removal of methyl groups, double bond reduction) → cholesterol.

Rate-limiting enzyme

HMG-CoA reductase — highly regulated at transcriptional, translational, and post-translational levels.

Sterol-dependent regulation

HMG-CoA reductase gene expression is regulated by SREBP-2 (sterol regulatory element-binding protein 2).

SREBP-2 function

Senses cellular sterol levels → increases or decreases HMG-CoA reductase transcription.

Sterol-induced enzyme degradation

High sterol levels → HMG-CoA reductase is tagged for ubiquitination and proteasomal degradation.

Sterol-independent regulation

Controlled via AMPK and phosphatase activity; phosphorylated form is inactive.

AMPK activation

Triggered by high AMP/low ATP → phosphorylates HMG-CoA reductase → inhibits cholesterol synthesis.

Hormonal regulation

Insulin and thyroxine ↑ HMG-CoA reductase expression; glucagon and glucocorticoids ↓ expression.

Major fates of cholesterol

Converted to bile acids, steroid hormones, or vitamin D.

Non-energy metabolite

Cholesterol is not oxidized for energy; all its carbons are retained in derivatives.

Bile acid function

Detergent-like compounds that emulsify dietary lipids in the intestine.

Bile acid synthesis

Occurs in the liver via multiple hydroxylation, saturation, and side-chain shortening steps.

Primary bile acids

Cholic acid (triol) and chenodeoxycholic acid — synthesized directly from cholesterol.

Structure of bile acids

24 carbons, 2–3 hydroxyl groups, and a terminal carboxyl group (pKa ~6).

Amphipathic nature

Bile acids have both polar and non-polar surfaces → effective emulsifiers.

Cholic acid synthesis

Rate-limiting step in bile acid formation.

Conjugation with amino acids

Bile acids are conjugated with glycine or taurine → bile salts (e.g. glycocholic acid, taurocholic acid).

Improved solubility

Bile salts are more amphipathic and better emulsifiers than unconjugated bile acids.

Bile salt presence

Only conjugated bile salts are secreted into bile.

Enterohepatic recycling

Bile salts secreted into bile → act in the intestine → reabsorbed in the ileum → returned to the liver via portal blood.

Transport mechanism

Reabsorption in ileum is via active transport.

Recycling benefit

Conserves bile salts and regulates cholesterol catabolism.

Cholesterol is precursor for

All five classes of steroid hormones: glucocorticoids, mineralocorticoids, androgens, estrogens, progestins.

Tissues involved

Adrenal cortex, ovary, testes, placenta.

Vitamin D precursor

7-dehydrocholesterol in skin → converted to cholecalciferol (vitamin D₃) via UV light.

Function of vitamin D

Regulates calcium and phosphate metabolism; supports bone health.

Statins mechanism

Inhibit HMG-CoA reductase → ↓ cholesterol synthesis → ↑ LDL receptor expression → ↓ serum LDL.

Liver’s central role

Synthesizes, stores, secretes, and degrades cholesterol.

Cholesterol homeostasis

Balanced by synthesis, dietary intake, excretion via bile, and conversion to bile acids.

Excess cholesterol

Associated with atherosclerosis, gallstones, and cardiovascular disease.

Cholesterol-lowering strategies

Include statins, bile acid sequestrants, dietary modification, and lifestyle changes.