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.

Quiz - Exam Preparation Strategy

When studying Quiz for your final board exams, it is critical to focus on the core concepts and fundamental formulas. Relying strictly on NCERT textbook solutions and practicing previous year questions (PYQs) is the proven methodology for scoring high marks. Avoid rote memorization and instead focus on the logical application of the theories presented in this chapter.

⚠️ Common Mistakes to Avoid

❓ Frequently Asked Questions

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Board exams tend to favor conceptual application questions and direct formula-based derivations from the NCERT syllabus. Ensure you have solved every single exercise in the official textbook.

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Yes, the NCERT textbook is the absolute gold standard for board exams. However, to improve your speed and accuracy during the actual exam, you must supplement your reading by solving timed mock tests and objective questions.