Cholesterol Metabolism Ashu.pptx

Cholesterol Metabolism OVERVIEW  Cholesterol, the characteristic steroid alcohol of animal tissues, performs a number of essential functions in the body.  For example, cholesterol is a structural component of all cell membranes, modulating their fluidity, and, in specialized tissues, cholesterol is a precursor of bile acids, steroid hormones, and vitamin D.  It is of critical importance that the cells of the body be assured an appropriate supply of cholesterol.  The liver plays a central role in the regulation of the body’s cholesterol homeostasis. It can also serve as a component of plasma lipoproteins sent to the peripheral tissues.  In humans, the balance between cholesterol influx and efflux is not precise, resulting in a gradual deposition of cholesterol in the tissues, particularly in the endothelial linings of blood vessels. This is a potentially life-threatening occurrence when the lipid deposition leads to plaque formation, causing the narrowing of blood vessels (atherosclerosis) and increased risk of cardio-, cerebro- and peripheral vascular disease.

STRUCTURE OF CHOLESTEROL • Cholesterol is a very hydrophobic compound. It consists of four fused hydrocarbon rings (A-D) called the “steroid nucleus”), and it has an eight-carbon, branched hydrocarbon chain attached to carbon 17 of the D ring. Ring A has a hydroxyl group at carbon 3, and ring B has a double bond between carbon 5 and carbon 6. • A. Sterols-Steroids with eight to ten carbon atoms in the side chain at carbon 17 and a hydroxyl group at carbon 3 are classified as sterols. Cholesterol is the major sterol in animal tissues. • B. Cholesteryl esters-Most plasma cholesterol is in an esterified form,which makes the structure even more hydrophobic than free (unesterified) cholesterol. Cholesteryl esters are not found in membranes, and are normally present only in low levels in most cells. Because of their hydrophobicity, cholesterol and its esters must be transported in association with protein as a component of a lipoprotein particle or be solubilized by phospholipids and bile salts in the bile

SYNTHESIS OF CHOLESTEROL • The major sites of synthesis of cholesterol are liver, adrenal cortex, testes, ovaries and intestine • The enzymes involved in the synthesis of cholesterol are partly located in the endoplasmic reticulum and partly in the cytoplasm. Step 1: Condensation- The acetyl CoA is provided by the ATP-citrate lyase reaction as in the case of fatty acid synthesis. Two molecules of acetyl CoA condense to form acetoacetyl CoA catalysed by cytoplasmic acetoacetyl CoA synthase. Step 2: Production of HMG CoA-A third molecule of acetyl CoA condenses with acetoacetyl CoA to form beta-hydroxy beta-methyl glutaryl CoA (HMG CoA). The enzyme is HMG CoA synthase. HMG CoA is present in both cytosol and mitochondria of liver. The mitochondrial pool is used for ketogenesis whereas the cytosolic fraction is utilized for cholesterol synthesis.

Step 3: The Committed Step-The reduction of HMG CoA to mevalonate is catalysed by HMG CoA reductase. It is a microsomal (endoplasmic reticulum) enzyme. It uses 2 molecules of NADPH .Steps 1 and 2 are shared with ketogenic pathway; but step 3 is the first reaction that is unique to the cholesterol biosynthetic pathway. It is the rate-limiting step. Step 4: Production of 5 Carbon Unit i. Mevalonate is successively phosphorylated to phospho-mevalonate, to pyrophosphomevalonate, then to 3phospho-5-pyrophosphomevalonate. ii. This then undergoes decarboxylation to give isopentenyl pyrophosphate, a 5 carbon unit. Step 4 requires 3 molecules of ATP. One molecule of CO2 is eliminated. Steps 1, 2, 3 and 4 together may be considered as the first phase of the cholesterol synthesis.