Human Biochemistry & Genetic

• Cholesterol


  • Component of cell membrane
  • Precursor for steroid hormone, bile salt, vitamin D
• Cholesterol


  • Derived from diet and de novo synthesis
  • Disposed by conversion to bile acids
  • Insoluble except when associated with bile salts and phospholipids
• Cholesterol

  • 27 carbon atoms from acetate moiety of acetyl CoA
  • Hydroxyl group esterified to fatty acid for transportation in lipoprotein and storage
• Synthesis of Cholesterol

  3 Phases: Conversion of acetyl CoA to HMG CoA, HMG-CoA to squalene, squalene to cholesterol
• Synthesis of Cholesterol

  Condensation of acetyl CoA to form acetoacetyl CoA, conversion to HMG-CoA, reduction to mevalonate, further conversions to cholesterol
• Synthesis of Cholesterol

  Geranylpyrophosphate + isopentenyl pyrophosphate = farnesyl pyrophosphate, squalene cyclizes to form lanosterol, lanosterol converted to cholesterol
• Esterification of Cholesterol

  65% of cholesterol in tissues esterified with long-chain fatty acids at C3, requires ATP, enzyme: acyl-CoA-cholesterol acyl transferase (ACAT)
• Regulation of Cholesterol Synthesis

  • Inhibitors of HMG-CoA reductase: Mevalonate, Compactin, Simvastatin, Pravastatin, Lovastatin
• Statins are agents for treating dyslipidemia, effective except when LDL receptor dysfunctional, inhibit HMG-CoA reductase
• Inhibitors of HMG-CoA reductase

  • Mevalonate
  • Compactin
  • Simvastatin (Zocor)
  • Pravastatin (Pravachol)
  • Lovastatin (Mevacor)
• Statins

  • Agents for treating dyslipidemia
  • Effective except when LDL (Low Density Lipoprotein) receptor dysfunctional
  • Inhibit HMG-CoA reductase
  • Reduce cholesterol and VLDL (Very Low Density Lipoprotein) synthesis in liver
• How statins work

  1. Higher the LDL receptors in liver, higher the plasma LDL-Cholesterol clearance

  2. Higher the atorvastatin and simvastatin, lower the triglyceride levels

  3. Some may increase HDL-Cholesterol levels (High density lipoprotein)
• Other potential effects of statins (cardioprotective effects)

  • On endothelial cell function: Increase nitric oxide synthesis
  • On plaque stability: Reduce degradation of matrix by metalloproteinases
  • On inflammation: Anti-inflammatory
  • On lipoprotein oxidation: Reduce oxidation of LDL and uptake by macrophages
  • On blood coagulation: Reduce platelet aggregation, Alter fibrinogen levels
• Mechanisms of statins

  1. Anti-inflammatory: Statin will cause the reduction of isoprenoids which give effects on G-protein, adhesion molecules, and cell proliferation

  2. Synthesis of steroid hormone
• Bile acids

  • Primary bile acid: CHOLIC & CHENODEOXYCHOLIC
  • Secondary bile acid: DEOXYCHOLATE & LITHOCHOLATE
• Primary bile acid is synthesized in hepatocytes directly from cholesterol and is the most abundant in humans
• Functions of bile acids

  1. Eliminating cholesterol

  2. Eliminate catabolites from liver through flow of bile

  3. Emulsifying lipids and fat-soluble vitamins in the intestine

  4. Reduction of bacteria in the small intestine and biliary tract

  5. Serves the purpose of breaking down fats
• Gallstones / Cholelithiasis occur due to increased concentration of cholesterol in bile, forming if cholesterol is precipitated out of solution around a core of protein and bilirubin located in the gall bladder
• Enterohepatic circulation of bile acids

  1. Bile acids released from gall bladder to intestine

  2. Primary bile acid converted to secondary bile acid by intestinal bacteria

  3. Both primary and secondary bile acid deconjugated and reabsorbed by intestinal mucosa

  4. Returned to the liver via the portal vein

  5. Bound to serum and albumin in the liver

  6. Liver takes up bile acids and reconjugates them with taurine or glycine

  7. Liver secretes the reconjugated bile acid in the bile