Cholesterol Metabolism and Biosynthesis

Cholesterol: Basics - Essential Waxy Molecule

• Waxy, fat-like substance (sterol); essential structural component of animal cell membranes.
• Structure: 27-carbon molecule with a tetracyclic steroid nucleus (cyclopentanoperhydrophenanthrene ring).
  • Amphipathic: Hydrophilic hydroxyl (-OH) group at C-3, hydrophobic body.
• Sources:
  • Dietary (exogenous): Animal products (e.g., meat, eggs, dairy).
  • De novo synthesis (endogenous): Primarily in liver; also intestine, adrenal cortex, gonads.
• Functions:
  • Maintains cell membrane fluidity & integrity.
  • Precursor for:
    • Bile acids (aid fat digestion).
    • Steroid hormones (e.g., cortisol, aldosterone, sex hormones).
    • Vitamin D.

⭐ Most plasma cholesterol is esterified with a fatty acid, forming cholesteryl esters, for transport and storage; this is catalyzed by ACAT (intracellular) and LCAT (plasma).

Cholesterol: Synthesis - From Acetate to Sterol

• Location: Cytosol (early reactions), Endoplasmic Reticulum (ER) for HMG-CoA Reductase & later steps.
• Substrate: Acetyl-CoA (provides all carbon atoms).
• Rate-Limiting Step (RLS): HMG-CoA conversion to Mevalonate by HMG-CoA Reductase (ER membrane, uses 2 NADPH).

  ⭐ HMG-CoA Reductase: Key regulatory point; target of statin drugs; inhibited by cholesterol, mevalonate; activated by insulin.

• Key Conversions:
  • Mevalonate (6C) $\rightarrow$ Isopentenyl Pyrophosphate (IPP - 5C) (requires ATP, involves decarboxylation).
  • IPP $\rightleftharpoons$ Dimethylallyl Pyrophosphate (DMAPP - 5C) (isomerization).
  • IPP + DMAPP $\rightarrow$ Geranyl-PP (10C) $\rightarrow$ Farnesyl-PP (FPP - 15C).
  • 2 FPP molecules condense to Squalene (30C) via Squalene Synthase (ER, requires NADPH).
  • Squalene is converted to Lanosterol (30C, the first sterol) via Squalene Epoxidase (ER, requires O2, NADPH) and Lanosterol Cyclase.
  • Lanosterol $\rightarrow$ Cholesterol (27C) through multiple (approx. 19) enzymatic steps in the ER (e.g., demethylations, double bond shifts).

Cholesterol: Regulation - The Control System

• Key Enzyme: HMG-CoA Reductase (HMGCR); ER-bound, rate-limiting.
• HMGCR Regulation:
  • Feedback: ↑Cholesterol inhibits HMGCR activity & ↓SREBP-2 mediated transcription.
  • Hormonal:
    • Insulin, Thyroxine: ↑HMGCR (dephosphorylation, ↑transcription).
    • Glucagon, Cortisol: ↓HMGCR (phosphorylation, ↓transcription).
  • Transcriptional (SREBP-2):
    • Low cholesterol → SREBP-2 active → ↑HMGCR gene expression.
    • High cholesterol → SREBP-2 inactive → ↓HMGCR gene expression.
  • Covalent: Dephosphorylated (Active) ↔ Phosphorylated (Inactive by AMPK).
  • Degradation: ↑Sterols → ↑HMGCR proteolysis.
• Drugs: Statins (e.g., Atorvastatin) competitively inhibit HMGCR. 📌 "Statins Stop HMGCR".

⭐ Statins competitively inhibit HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis, effectively lowering plasma cholesterol.

Cholesterol: Transport & Fate - Delivery and Destiny

• Transport & Delivery: 📌 LDL: "Leaves Da Cholesterol"; HDL: "Helps Da Liver".
  • LDL (Low-Density Lipoprotein): "Bad cholesterol"; delivers hepatic cholesterol to peripheral tissues. ApoB-100 mediated.
  • HDL (High-Density Lipoprotein): "Good cholesterol"; Reverse Cholesterol Transport (RCT) to liver. Key: LCAT (Lecithin-Cholesterol Acyltransferase), ApoA-I (LCAT activator).
  • CETP (Cholesteryl Ester Transfer Protein): Exchanges HDL's cholesteryl esters (CE) for VLDL/IDL's triglycerides (TG).
• Cellular Uptake & Storage:
  • LDL receptor (LDL-R) mediated endocytosis.
  • Stored as cholesteryl esters by ACAT (Acyl-CoA Cholesterol Acyltransferase) enzyme.
• Metabolic Fates (Utilization):
  • Bile Acid Synthesis: Major elimination pathway in liver. Rate-limiting enzyme: Cholesterol 7α-hydroxylase (CYP7A1).
  • Steroid Hormone Synthesis: Precursor for all steroid hormones (e.g., cortisol, aldosterone, sex hormones).
  • Vitamin D Synthesis.
  • Cell Membrane Component: Essential for structure and fluidity.
• Excretion:
  • Primarily as bile acids and neutral sterols (unmodified cholesterol) in feces.

  ⭐ Familial Hypercholesterolemia (FH) is an autosomal dominant disorder, most commonly due to LDL receptor defects, leading to markedly ↑LDL-C levels and premature atherosclerosis.

High‑Yield Points - ⚡ Biggest Takeaways

• HMG-CoA reductase is the rate-limiting enzyme in cholesterol biosynthesis, targeted by statin drugs.
• All carbons of cholesterol are derived from Acetyl-CoA; synthesis occurs mainly in the liver.
• LDL delivers cholesterol to peripheral tissues; HDL mediates reverse cholesterol transport.
• Familial Hypercholesterolemia results from LDL receptor defects, causing ↑ plasma LDL.
• Cholesterol is the precursor for bile acids, steroid hormones, and Vitamin D.
• 7α-hydroxylase is the rate-limiting enzyme for bile acid synthesis from cholesterol.