بسم الله الرحمن الرحيم

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

13. 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

14. Regulation of Cholesterol Synthesis CONT’D

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

16. 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

18. Bile Acids: Synthesis

19. 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

21. 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

22. Enterohepatic Circulation

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

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