Cholesterol Metabolism
- Cholesterol is an organic compound containing a four sterol ring – 27C
- contains primarily carbon and inert rings – very stable
- it is an isoprenoid – derived from isoprene
- other isoprenoids: dolichol and ubiquinone
Synthesis of Cholesterol
(1) Production of HMG CoA – from condensation of acetoacetyl CoA with acetyl CoA via HMG CoA synthase
- exactly like first step in ketone body synthesis, but occurs in the cytosol not the mitochondria
(2) Reduction of HMG CoA to mevalonic acid – involves reduction of thioester carbon to primary alcohol using NADPH
- HMG CoA reductase
catalyzes this – rate limiting step in cholesterol synthesis, target of anti-cholesterol therapy (statins are competitive inhibitors)
(3) Activation of Mevalonic Acid to Isopentyl Pyrophosphate – uses 3 ATP – building block of all Isoprenoids
- 2 ATP phosphorylate terminal alcohol group of mevalonic acid
- another ATP to decarboxylate/add double bond
(4) Polymerization of Isoprenol Pyrophosphate to Squalene (30C) – 6 isoprenol units
(5) Formation of Lanosterol from Squalene – in a single step – lanosterol looks like cholesterol
- uses a monooxygenase to produce an epoxide – first sterol synthesized
(6) Formation of Cholesterol from Lanosterol – demethylation, double bonds added
- this step involves 19 separate enzymatic reactions – more than glycolysis
Uses of Cholesterol
(1) Formation of Bile Acids in liver – the major physiological use of cholesterol – secrete 15-30 g/day through bile duct
- bile acids (e.g., glycocholate) are flat detergents used to solubilize fats for absorption into the small intestine
- 90-95% cholesterol is reabsorbed in the intestine and delivered back to the liver – enterohepatic circulation
- aid in breaking up TG in micelles - Ý surface area for pancreatic lipase
(2) Production of Hormones – primarily for gonads and adrenal cortex – can activate receptors at very low concentration
(3) Production of Vitamin D – requires a photon – vitamin D must come from diet if not enough time is spent in the sun
(4) Stabilization of Membranes – cholesterol makes membranes more rigid
- there is more cholesterol than phosopholipids in RBC membranes!
Fates of Cholesterol
(1) Esterification – makes it hydrophobic, removing it from the active pool (storage form – reversable)
- in mitochondria and endoplasmic reticulum: ACAT (acyl CoA cholesterol acyl transferase); in blood: LCAT (lecithin cholesterol acyl transferase)
(2) Excretion in feces – about 0.5 g/day