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Cholesterol Metabolism - Overview, Functions, and Regulation

This article provides an overview of cholesterol metabolism, including its functions, synthesis, regulation, and degradation. It also discusses the role of bile acids and salts, as well as the enterohepatic circulation. Additionally, it covers the types of cholesterol and their synthesis in various tissues.

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Cholesterol Metabolism - Overview, Functions, and Regulation

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  1. بسم الله الرحمن الرحيم

  2. Cholesterol Metabolism By Amr S. Moustafa, M.D.; Ph.D.

  3. Outlines • Overview and Functions • Liver cholesterol pool • Structure and Types • Synthesis and Regulation • Bile acids and salts • Enterohepatic circulation

  4. Overview and Functions • MajorSterol of animal tissues • Component of cell membranes • Precursor for: Bile acids & salts Vitamin D Steroid hormones: Mineralocorticoids e.g., Aldosterone Glucocorticoids, e.g., Cortisol Sex hormones, e.g., Testosterone Estrogen & progesterone • Hypercholesterolemia:Atherosclerosis & CAD

  5. Liver Cholesterol Pool

  6. Cholesterol: Structure

  7. Cholesterol: Types Animal and plant sterols: Animal sterol:Cholesterol Plant sterol:β-Sitosterol Poor intestinal absorption  Active transport to intestinal lumen  Block cholesterol absorption  Dietary treatment of hypercholesterolemia (Trans fatty acid-free margarine)

  8. Cholesterol: Types CONT’D

  9. Cholesterol: Synthesis • All tissues, e.g., Liver, Intestine, Adrenal cortex, & Reproductive organs • Cytosol & ER • Building blocks: Acetyl CoA • Reducing equivalents: NADPH • Thioester bond &ATP • Rate-limiting enzyme: HMG CoA reductase

  10. Cholesterol: Synthesis CONT’D CONT’D

  11. Cholesterol: Synthesis CONT’D CONT’D Internsic ER membrane Catalytic domain, cytosol

  12. Regulation of Cholesterol Synthesis (A) HMG CoA gene expression: • Sterol-dependent: • Cholesterol content • SREBP • Stability of mRNA & HMG CoA protein • Hormonal-dependent:Insulin (+), Glucagon (-) • (B) Phosphorylation/dephosphorylation: • Sterol-independent, Hormonal-dependent • Dephospho-form:Active (C) Statin drugs:Reversible, competitive inhibitors

  13. Regulation of Cholesterol Synthesis CONT’D

  14. Cholesterol: Degradation Intact sterol nucleus: Bile acids & salts  Cholesterol secretion into bile: Cholesterol Coprostanol Choleastanol Reduced products Bacteria Neutral fecal sterols

  15. Bile Acids and Salts Bile acids: 24 C, 2 or 3 OH -COOH at side chain Amphipathic, Emulsifying agents Primary bile acids: Cholic acidandChenodeoxycholic acid Glycochenodeoxycholic Taurochenodeoxycholic Glycocholic Taurocholic Bile salts (Conjugated bile acids): amide-linked with glycine or taurine

  16. Bile Acids: Synthesis

  17. Bile Salts • More effective detergent • -COOH (glycine) & -SO4 (taurine): Fully-ionized • Only bile salts, but not acids, found in bile • Important for cholesterol excretion: metabolic products Solubilizer for cholesterol in bile • Genetic deficiency: Exogenous bile acids

  18. Secondary Bile Acids Bile salts Glyco- or Tauro-cholic -Chenodeoxycholic Glycine Intestinal bacteria Taurine Bile acids Cholic acid Chenodeoxycholic Intestinal bacteria OH 2° Bile acids Deoxycholic acid Lithocholic

  19. Enterohepatic Circulation

  20. Cholelithiasis Causes: bile salts in bile: malabsorption syndrome Biliary tract obstruction hepatic dysfunction Biliary cholesterol excretion Treatment: Bile acid replacement therapy  Surgical

  21. Hypercholesterolemia Cholesterol blood level: Familial Hypothyroidism Diabetes mellitus Nephrotic syndrome Obstructive jaundice Treatment: Dietetic Bile acid sequestrants, e.g., Cholestyramine Statin drugs

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