Lec 30 Cholesterol Metabolism PDF

Lippincott’s illustrated reviews Chapter 18 – Page 219 Lecture 30 Cholesterol metabolism 1  Specific Objectives By the end of this lecture students can be able to: Understand the importance of cholesterol inside the body. Understand the action of int...

Lippincott’s illustrated reviews Chapter 18 – Page 219 Lecture 30 Cholesterol metabolism 1  Specific Objectives By the end of this lecture students can be able to: Understand the importance of cholesterol inside the body. Understand the action of intestinal flora on bile salts. Explain the effect of bile salt deficiency (Cholelithiasis). 2 3  Cholesterol, the characteristic steroid alcohol of animal tissues. 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. 4  The liver plays a central role in the regulation of the body’s cholesterol homeostasis. Cholesterol enters the liver from a number of sources including dietary cholesterol, as well as cholesterol synthesized de novo by extrahepatic tissues and by the liver itself. Cholesterol is eliminated from the liver as unmodified cholesterol in the bile, or it can be converted to bile salts that 5 are secreted into the intestinal lumen.  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 6 of blood vessels.  Lipid deposition leads to plaque formation, causing the narrowing of blood vessels (atherosclerosis) and increased risk of cardio-, cerebro- and peripheral vascular disease. 7  Biosynthesis of Cholesterol The major sites of synthesis of cholesterol are liver, adrenal cortex, testes, ovaries and intestine. All nucleated cells can synthesize cholesterol, including arterial walls. The enzymes involved in the synthesis of cholesterol are partly located in the endoplasmic reticulum and partly in the cytoplasm. 8  The regulatory enzyme is HMG CoA reductase. Insulin and thyroxin increase the activity of HMG CoA reductase. Cortisol and glucagon decrease its activity. Drugs: Lovastatin and other "statin" group of drugs are competitive inhibitors of HMG CoA reductase. So, they are used in clinical practice to reduce cholesterol level in blood. 9  BILE ACIDS AND BILE SALTS Bile consists of a watery mixture of organic and inorganic compounds. Phosphatidylcholine (lecithin) and bile salts (conjugated bile acids) are quantitatively the most important organic components of bile. Bile can either pass directly from the liver where it is synthesized into the duodenum through the common bile duct, or be stored in the gallbladder when not immediately needed for digestion. 10 Action of intestinal flora on bile salts Bacteria in the intestine can remove glycine and taurine from bile salts, regenerating bile acids. They can also convert some of the primary bile acids into “secondary” bile acids by removing a hydroxyl group, producing deoxycholic acid from cholic acid and lithocholic acid from chenodeoxycholic acid. 11 12 Bile salt deficiency: cholelithiasis Precipitation of cholesterol in the gallbladder, leading to cholesterol gallstone disease— cholelithiasis. 13 14  This disorder is typically caused by a decrease of bile acids in the bile, which may result from: 1) gross malabsorption of bile acids from the intestine, as seen in patients with severe ileal disease; 2) obstruction of the biliary tract, interrupting the enterohepatic 15 circulation; 3) severe hepatic dysfunction, leading to decreased synthesis of bile salts, or other abnormalities in bile production; or 4) Excessive feedback suppression of bile acid synthesis as a result of an accelerated rate of recycling of bile acids. Cholelithiasis also may result from increased biliary cholesterol excretion, as seen with the use of fibrates. 16  Laparoscopic cholecystectomy (surgical removal of the gallbladder through a small incision) is currently the treatment of choice. However, for patients who are unable to undergo surgery, oral administration of chenodeoxycholic acid to supplement the body’s supply of bile acids results in a gradual (months to years) dissolution of the gallstones. 17 Reference Book: Champe, P. C., Harvey, R. A. and Ferrier, D. R., 2005. Biochemistry “Lippincott’s Illustrated Reviews”, 5th or 6th Edition 18