Cholesterol & Lipoproteins

Cholesterol & Lipoproteins

Cholesterol is a 27-carbon steroid essential for membrane structure and as a precursor to steroid hormones, bile acids, and Vitamin D. It is synthesized in the liver (primarily) and all nucleated cells.

Cholesterol Synthesis

Site: Cytosol and SER. All carbons come from Acetyl-CoA.

  1. 3 Acetyl-CoA → HMG-CoA [HMG-CoA Synthase, in cytosol — different from mitochondrial enzyme for KB]
  2. HMG-CoA → Mevalonate + CoA [HMG-CoA Reductase — Rate-limiting step; requires 2 NADPH; target of Statins]
  3. Mevalonate → Isopentenyl pyrophosphate (via phosphorylation steps; requires 3 ATP)
  4. 6 Isoprene units → Squalene (C30)
  5. Squalene → Lanosterol (cyclization, requires O₂)
  6. Lanosterol → Cholesterol (19 more steps)

Statins: Competitive inhibitors of HMG-CoA Reductase → ↓cholesterol synthesis → ↑LDL receptor expression → ↑LDL uptake → ↓serum LDL.

Regulation of Cholesterol Synthesis

  • HMG-CoA Reductase inhibited by: Cholesterol (end-product feedback), PCSK9 (promotes LDL receptor degradation)
  • Activated by: Insulin. Inhibited by: Glucagon, Statins
  • SREBP (Sterol Regulatory Element-Binding Protein): transcription factor; activated when cholesterol is low → induces HMG-CoA Reductase and LDL receptor genes

Lipoproteins

Lipoproteins are spherical particles that transport hydrophobic lipids in blood. Structure: Hydrophobic core (TG, CE) + Amphipathic shell (phospholipids, free cholesterol, apolipoproteins).

  • Chylomicrons: Largest, lowest density. Made in intestinal enterocytes. Transport dietary (exogenous) fat. ApoB-48, ApoC-II, ApoE. Lipolyzed by LPL (activated by ApoC-II) in capillaries → remnants taken up by liver (ApoE → LRP receptor). Deficiency of LPL or ApoC-II → Type I hyperlipoproteinemia (pancreatitis, creamy plasma).
  • VLDL: Made in liver. Transport endogenous TG. ApoB-100, ApoC-II, ApoE. Lipolyzed by LPL → IDL → LDL.
  • LDL (Low-Density Lipoprotein): ApoB-100 only. Carries cholesterol to peripheral tissues. LDL receptor (B100) mediates endocytosis. "Bad Cholesterol". Elevated in Familial Hypercholesterolemia (FH: LDL receptor mutation).
  • HDL (High-Density Lipoprotein): Synthesized by liver and intestine. "Good Cholesterol". ApoA-I is major apolipoprotein. Collects cholesterol from tissues (Reverse Cholesterol Transport). Transfers CE to other lipoproteins via CETP. ApoA-I activates LCAT (Lecithin-Cholesterol Acyl Transferase) → esterifies cholesterol on HDL surface.

Key Apolipoproteins

  • ApoA-I: HDL; activates LCAT
  • ApoB-100: VLDL, IDL, LDL; LDL receptor ligand
  • ApoB-48: Chylomicrons (truncated B-100)
  • ApoC-II: Activates LPL (endothelial)
  • ApoE: Ligand for remnant and LDL receptors; ApoE4 allele → ↑Alzheimer's risk

Reverse Cholesterol Transport

Nascent HDL (disk-shaped) → picks up free cholesterol from cells via ABC-A1 transporter → LCAT esterifies it (CE) → HDL3 → HDL2 (mature, spherical) → delivers CE to liver via SR-B1 receptor or transfers to LDL via CETP → liver excretes as bile.