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Cholesterol synthesis and breakdown

Cholesterol synthesis and breakdown. Dr. Carolyn K. Suzuki. Cholesterol in cellular membranes. Lippincott, Fig. 18-2. A. Synthesis of HMG CoA. Cytosol Mitochondria Peroxisomes. Lippincott, Fig. 18-3. A. Synthesis of mevalonic acid. Endoplasmic reticulum. Lippincott, Fig. 18-4.

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Cholesterol synthesis and breakdown

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  1. Cholesterol synthesis and breakdown Dr. Carolyn K. Suzuki

  2. Cholesterol in cellular membranes

  3. Lippincott, Fig. 18-2

  4. A. Synthesis of HMG CoA Cytosol Mitochondria Peroxisomes Lippincott, Fig. 18-3

  5. A. Synthesis of mevalonic acid Endoplasmic reticulum Lippincott, Fig. 18-4

  6. C. Cholesterol synthesis

  7. The transcription factor regulating cholesterol synthesis genes is SREBP- sterol responsive element binding protein

  8. 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 11 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 2- localized 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

  9. nucleus

  10. step #1 when sterol levels are low SCAP and SREBP are transported to the Golgi 13

  11. step #2 SREBP release step #3

  12. step #4 nucleus SREBP translocates to nucleus transcriptional activation of sterol responsive element (SRE) controlled genes

  13. When intracellular cholesterol is low

  14. Cholesterol-dependent degradation of HMG CoA reductase

  15. (AMP kinase)

  16. 20

  17. 21

  18. Statins competitively inhibit HMGR- they mimic the transient intermediate mevadyl CoA

  19. Zetia (ezetimibe) • Mechanism of action- • acts at small intestine brush border • inhibits absorption of cholesterol • does not block absorption of triglycerides or fat- soluble vitamins 23 Vytorin (ezetimibe + simvastatin) • ezetimibe administered in combination with a simavastatin (i.e. a statin) • further reduces total cholesterol levels as compared to statin treatment alone • blocks cholesterol absorption in the intestine and cholesterol synthesis in the liver • permits reduced doses of statins, which have side effects

  20. Bile acids and bile salts- elimination of cholesterol • ring structure of cholesterol cannot be broken down into CO2 and H2O • cholesterol is used to produce bile acids and bile salts, which are: • synthesized in the liver • stored in the gall bladder • secreted into intestine as bile- a watery mixture of organic and inorganic compounds, phosphatidylcholine, bile acids and salts • emulsifies dietary lipids • ~5% of bile salts is excreted in feces • ~95% is reabsorbed in gut and returned to liver 25

  21. The two primary bile acids, synthesized in liver- cholic acid (31%) chenodeoxycholic acid (45%) • emulsify dietary lipids making them accessible to pancreatic lipases, thereby aiding digestion • facilitate the intestinal absorption of fat-soluble vitamins (A, D, E, K) • negatively regulate their own metabolism • bile acids bind to cellular receptors-regulate lipid metabolism, glucose metabolism and overall energy expenditure

  22. Bile salts are- • formed in the liver from bile acids • conjugated to glycine or taurine more amphipathic than bile acids more effective detergents than bile acids • secreted into the intestine/duodenum • resorbed in the ileum and returned to the liver • eliminated in feces at low levels • the principal mechanism for eliminating • cholesterol from the body • hypercholesterolemia is often treated with- compounds that sequester bile acids in the intestine, which prevent reabsorbtion of bile acids increase elimination in feces increase conversion of cholesterol to bile acids 27 dietary fiber also sequesters bile acids

  23. 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?

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