8 cholesterol metabolic pathway and its abnormalities

cholesterol is an important constituent of the body and hyper cholesterolemia has important clinical impact on the body

1. CHOLESTEROL METABOLISM

2. CHOLESTEROL

3. Cholesterol Synthesis Perhydrocyclopentanophenanthrene structure consists of four fused rings Cholesterol contains a hydroxyl group at C3, double bond between C5 & C6, eight-membered hydrocarbon chain at C17, & methyl groups at C10 & C13 Cholesterol Perhydrocyclopentanophenanthrene Fig. 1 Fig.2

4. CHOLESTEROL

5. FUNCTIONS OF CHOLESTEROL

6. CHOLESTEROL BIOSYNTHESIS

7. All the carbon atoms of cholesterol are derived from acetyl CoA Liver and Intestine are major sites of cholesterol

8. STEPS OF DE NOVO CHOLESTEROL SYNTHESIS Step 1—Biosynthesis of Mevalonate Step 2—Formation of Isoprenoid Units Step 3—Six Isoprenoid Units Form Squalene Step 4—Formation of Lanosterol Step 5—Formation of Cholesterol

9. 2 Acetyl-CoA Acetoacetyl-CoA HMG-CoA Mevalonate Several steps

10. 3 Acetyl-CoA HMG-CoA Mevalonate Isopentenyl pyrophosphate X6 Squalene Lanosterol Cholesterol C 6 C 5 C 30 C 30 C 27

11. Cholesterol Synthesis Stage I: Acetyl CoA to Mevalonate A. B. C. Rate limiting step Fig.3

12. Cholesterol Synthesis Stage 2: Mevalonate to 2 Activated Isoprenes Transfer 3 ATP to Mevalonate in order to activate C5 & OH-group of C3 Phosphate group at C3 & Carboxyl group of C1 leave, which produces a double bound This allows for two active isoprenes Fig.5

13. Cholesterol Synthesis Stage 3: Condensation of Isoprenes to for Squalene 1) Head to tail attachment of isoprenes to form Geranyl pyrophosphate 2) Head to tail condensation of Geranyl pyrophosphate and isopentenylpyrophosphate to form Farnesyl pyrophosphate 3) Head to head fusion of two Farnesyl pyrophosphate to form squalene Fig.6

14. Cholesterol Synthesis Stage 4: Squalene to Four-Ring Steroid Nucleus Squalene monooxygenase adds oxygen to form an epoxide Unsaturated carbons (double bonds) are aligned to allow cyclization and formation of lanosterol After many reaction get cholesterol Fig. 7

15. Fates of Cholesterol Membranes Cholesterol Ester Biliary Cholesterol Bile Acids

16. Cholesterol Esters Acyl-CoA:cholesterol acyl transferase (ACAT) is an ER membrane protein ACAT transfers fatty acid of CoA to C3 hydroxyl group of cholesterol Excess cholesterol is stored as cholesterol esters in cytosolic lipid droplets Fig. 8

17. Bile Salts Bile acids & salts are effective detergents Synthesized in the liver Stored & concentrated in the gallbladder Discharged into gut and aides in absorption of intraluminal lipids, cholesteral, & fat soluble vitamines Bile acid refers to the protonated form while bile salts refers to the ionized form The pH of the intestine is 7 and the pKa of bile salts is 6, which means that 50% are protonated These terms are sometimes used interchangeably

18. Synthesis of Bile Salts Rate-limiting step performed by the 7α-hydroxylase (CYP7A1) and is regulated by bile salt concentration End product: Cholic acid series & Chenocholic acid series Bile salts can be conjugated & become better detergents Fig. 9 Fig. 10

19. Regulation of de novo synthesis of cholesterol

20. Cholesterol Synthesis Stage I: Regulation by Covalent Modification Short-term regulation by phosphorylation & dephosphorylation Adenosine monophosphate (AMP) activated kinase phosphorylates HMG-CoA Glucagon, sterols, glucocorticoids & low ATP levels inactivate HMG-CoA Insulin, thyroid hormone, high ATP levels activate enzyme Fig. 4C

21. HMG-CoA reductase (active) HMG-CoA reductase (Inactive) Acetyl-CoA HMG-CoA Mevalonate CHOLESTEROL Insulin Glucagon Increased caloric intake, Thyroid hormone Bile acids, glucocorticoids, Dietary cholesterol P Dephosphorylation Phosphorylation + + + -

22. Competitive inhibitor drugs of HMG-CoA REDUCTASE

23. IMPORTANT COMPUNDS SYNTHESIZED FROM CHOLESTEROL

24. CHOLESTEROL-BIOLOGICAL IMPORTANT COMPONDS

25. FORMATION OF BILE ACIDS Bile acids are synthesized in the liver from cholesterol. They contain 24 carbon atoms

26. Cholesterol 7-α- hydroxyl cholesterol Bile acids Vitamin C O 2 H 2 O 7-α- hydroxylase

27. FORMATION OF STEROID HORMONES Cholesterol Progesterone Androgens Estrogens Glucocorticoids Mineralocorticoids

28. Cholesterol 7-dehydrocholesterol CHOLECALCIFEROL [Vitamin D 3 ] UV light Dehydrogenase FORMATION OF VITAMIN D

29. BLOOD CHOLESTEROL

30. EXCRETION OF CHOLESTREROL Cholesterol is excreted in faeces Cannot be destroyed by oxidation to CO 2 and H 2 O, because of absence of enzyme capable of catabolising the steroid nucleus About 1gm of cholesterol is eliminated from the body per day

31. DISORDER OF CHOLESTEROL METABOLISM