Transcript Document
Cholesterol synthesis and breakdown Dr. Carolyn K. Suzuki 1 OBJECTIVES To compare and contrast the different mechanisms by which cholesterol biosynthesis are regulated. To predict whether intracellular cholesterol synthesis will be up- or down-regulated in response to energy availability as influenced by diet, hormones and exercise. To distinguish the different mechanisms by which plasma cholesterol levels are controlled by clinically adminstrered pharmacological agents. 2 Cholesterol in cellular membranes 3 4 5 Cholesterol •27 carbons all derived from acetate •C-3 hydroxyl group •C-17 side chain with 8 carbons cholesterol Sources in the body • synthesized primarily in liver and intestine • not required in diet • intestinal uptake from diet hydrocarbon tail C A D steroid nucleus B Elimination • converted into bile acids and bile salts in liver • stored in gall bladder, secreted into intestine • small % excreted in feces 21 Cholesterol esters • esterification at C-3 with fatty acid • primary form transported in plasma • packaged in lipoprotein particles (e.g. LDL, HDL) 26 cholesterol ester C 3 A D B fatty acid 6 A. Synthesis of HMG CoA 2 acetyl CoA (2C) thiolase cytosol mitochondria peroxisomes CoA 2 acetoacetyl CoA (4C) HMG CoA synthase acetyl CoA CoA 3-hydroxy-3-methylglutaryl CoA (6C) (HMG CoA) 7 B. Synthesis of mevalonic acid HMG CoA (6C) 2 NADPH RATE LIMITING STEP HMG CoA reductase CoA 2 NADP+ endoplasmic reticulum Mevalonic acid (6C) 8 C. Cholesterol synthesis 9 C. Cholesterol synthesis 10 The transcription factor regulating cholesterol synthesis genes is SREBP- sterol responsive element binding protein 11 Sterol-dependent regulation of cholesterol synthesis genes SREBP- Sterol Regulatory Element Binding Protein a transmembrane protein has a DNA binding domain has a SCAP interacting domain SCAP- SREBP Cleavage Activating Protein a transmembrane protein has a sterol sensing domain binds to SREBP in the ER when ER sterols are low, SCAP-SREBP move to the Golgi Protease 1 and Protease 2localized to the Golgi responsible for the two step cleavage of SREBP resulting in soluble, cytosolic SREBP Mature, proteolytically-processed SREBP translocates from the Golgi to the nucleus activates the expression of cholesterol synthesis genes 12 nucleus 13 14 step #1 when sterol levels are low SCAP and SREBP are transported to the Golgi 15 step #2 SREBP release step #3 16 step #4 SREBP translocates to nucleus nucleus transcriptional activation of sterol responsive element (SRE) 17 controlled genes When intracellular cholesterol is low 18 19 Cholesterol-dependent degradation of HMG CoA reductase 20 (AMP kinase) AMP kinase is different from cAMP-dependent kinase (PKA) 21 22 23 Statins competitively inhibit HMGRthey mimic the transient intermediate mevadyl CoA 24 Zetia (ezetimibe) Mechanism of action• acts at small intestine brush border • does not enter the bloodstream, no side effects • inhibits absorption of cholesterol • does not block absorption of triglycerides or fat-soluble vitamins Vytorin (ezetimibe + simvastatin) • ezetimibe administered in combination with a simavastatin (i.e. a statin) • further reduces total cholesterol levels as compared to statin alone • blocks cholesterol absorption in the intestine and cholesterol synthesis in the liver • permits reduced doses of statins, which have side effects 25 Reduction of LDL-cholesterol across all tested statins Mean % change in LDL-C from baseline 26 Bile acids and bile salts • cholesterol is the precursor of bile acids and bile salts • synthesized in the liver • stored in the gall bladder • secreted into intestine • aids digestion by emulsifying dietary lipids making them accessible to pancreatic lipases • aids intestinal absorption of fat-soluble vitamins (A, D, E, K) • ~95% are reabsorbed in ileum and returned to liver • ~5% of bile salts are excreted in feces Enterohepatic circuit •synthesis in the liver •storage in the gall bladder •secretion into intestine •re-circulation to liver Excretion of bile salts is the principal mechanism for eliminating cholesterol from the body 27 Primary bile acids are formed from cholesterol 7-a-hydroxylase rate limiting step + cholesterol - cholic acid cholic acid cholesterol hydroxylation of C7 addition of OH group 7-a-hydroxycholesterol chenodeoxycholic acid 28 7-a-hydroxylase Primary bile acids - cholic acid + cholesterol 29 7-a-hydroxylase Primary bile acids + cholic acid cholesterol Secondary bile acids • Hypercholesterolemia is often treated with “sequestrants” that bind bile acids in the intestine. These compounds: prevent reabsorbtion of bile acids increase conversion of cholesterol to bile acids increase bile salt elimination in feces • Dietary fiber also sequesters bile acids 30 Increased elimination of cholesterol from the body Primary bile acids Secondary bile acids Bile saltsglycine or taurine conjugated to bile acids in liver 5% lost in feces Recent R & D efforts focusing on bile acid receptors as drug targets for treating liver disease, liver cancer, metabolic disease. Review- you tell me !!!! •How many carbons are there in cholesterol? •Which carbons are the business ends of the cholesterol molecule? •When cholesterol levels are high, HMG CoA reductase is regulated by which of the following mechanisms? •When cholesterol levels are high, HMG CoA reductase is regulated by which of the following mechanisms? •What organ STORES bile acids and bile salts?