Cholesterol Synthesis in the Liver: Pathway, Regulation, and Systemic Role

The liver is the primary site of de novo cholesterol synthesis (~1 g/day), accounting for ~20% of total body synthesis; intestines, adrenals, skin contribute the rest.

Synthetic Pathway (Mevalonate Pathway)

1. Acetyl-CoA → HMG-CoA (cytosol)
2. HMG-CoA → Mevalonate (via HMG-CoA reductase – rate-limiting, statin target)
3. Mevalonate → Isoprenoids → Squalene → Lanosterol → Cholesterol (20+ steps)

Regulation

• Feedback: Cellular cholesterol ↓ HMG-CoA reductase transcription (via SREBP-2) and promotes enzyme degradation.
• Hormonal: Insulin ↑ synthesis; glucagon, thyroid hormone ↓ synthesis.
• Dietary: High cholesterol intake ↓ hepatic synthesis (partial compensation).

Hepatic Cholesterol Disposition

• Secreted into bile (free or as bile acids after CYP7A1 conversion).
• Packaged into VLDL → LDL for peripheral delivery.
• HDL mediates reverse cholesterol transport back to liver.
• Stored as cholesteryl esters in lipid droplets.

The liver thus maintains whole-body cholesterol homeostasis via synthesis, lipoprotein secretion, bile acid excretion, and receptor-mediated uptake (LDL receptor).