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- 1. Cholesterol Metabolism Dr Marwa Matboli Dr Walaa Ibrahim Dr Heba Morsi Assistant professor of medical biochemistry & molecular biology
- 3. Intended Learning Outcomes By the end of this lecture , the student should be capable of: • List different types of Steroid lipids. • Describe the role of some steroids. • Identify the structure of some steroids. • Summarize the synthesis and degradation of steroids. • Explain the steps of bile synthesis. • Describe some abnormalities in Steroid lipid metabolism
- 5. Steroids Compounds with 19 C Two CH3 (C19&18) attached to (C10&C13) Steroids containing hydroxyl groups are often referred to as sterols
- 6. Generally, there are 2 groups of sterols Animal sterols (cholesterol) Plant sterols (phytosterols) As cholesterol in having OH at C3 Are poorly absorbed by humans It is converted to Vit D2(ergocalciferol) under the skin by the action of UV
- 7. Structure Sources Function Site of Biosynthesis Steps Regulation Plasma cholesterol Excretion Biochemical derivatives of cholesterol Bile salts
- 8. Cholesterol is the main steroid in the body(27C) A nonpolar hydrocarbon body The steroid nucleus with an 8- hydrocarbon side chain at C-17 It has OH at carbon 3.
- 9. Sources of cholesterol A little more than half the cholesterol of the body arises by synthesis (about 700 mg/dl), Only a little portion of the body cholesterol is derived from diet Vegetable Oil Contains no cholesterol
- 10. The liver plays a central role in the regulation of the body's cholesterol homeostasis. There is a critical balance between the rate of cholesterol synthesis in the body and rate of cholesterol excretion.
- 11. • Cholesterol is widely distributed in all cells of the body but particularly abundant in nervous tissue. • Precursor of all steroids in the body (Steroid hormones & Bile Acids)
- 12. Structure Sources Function Site of Biosynthesis Steps Regulation Plasma cholesterol Excretion Biochemical derivatives of cholesterol Bile salts
- 13. Liver Intestine Major sites for cholesterol biosynthesis
- 14. Substrates Acetyl CoA (From Pyruvate or FA oxidation) NADPH (Cofactor)
- 15. Fates of Acetyl CoA Krebs Cycle Energy Production Well Fed FA synthesis Cholesterol Synthesis Fasting Ketone body synthesis Alternative pathway for energy production
- 17. There are 2 isoenzymes of HMG CoA synthase Cytosolic Cholesterol Synthesis Mitochondrial Ketogenesis
- 19. ATP dependent decarboxylation Condensation (IPP x 6) Cyclization
- 20. Synthesis of Mevalonate by HMG-CoA reductase Mevalonate is then activated by two successive phosphorylation (catalyzed by kinases) yielding mevalonate 5-diphosphate HMGR is the rate limiting step of cholesterol biosynthesis Requires two NADPH as a cofactor HMGR bound in the endoplasmic reticulum HMG-CoA is then converted to mevalonate by HMG-CoA reductase mevalonate 5-diphosphate 2ATP 2ADP kinases
- 21. Isopentenyl pyrophosphate (IPP) Synthesis Following the formation of mevalonate 5-diphosphate ATP-dependent decarboxylation yields isopentenyl pyrophosphate (IPP) Which is an activated isoprenoid molecule
- 22. Condensation of 6 activated isoprene unit to form squalene(30C) 6
- 23. Squalene to cholesterol Squalene undergoes a two-step cyclization to yield lanosterol catalyzed by hydroxylase and cyclase Conversion of lanosterol to cholesterol involves 19 reactions, catalyzed by enzymes in ER membranes A sequence of reactions using molecular oxygen and NADPH occurs
- 24. ATP dependent decarboxylation Condensation (IPP x 6) Cyclization
- 25. Structure Sources Function Site of Biosynthesis Steps Regulation Plasma cholesterol Excretion Biochemical derivatives of cholesterol Bile salts
- 26. 2.Long Term Regulation (gene regulation) 1.Short Term Regulation ✓Feedback regulation ✓Covalent modification ✓Competitive inhibitors(Drugs)
- 27. Mevalonate (immediate product) Cholesterol (End product) Feedback Inhibition
- 28. Covalent regulation Glucagon & Epinephrine During fasting Insulin During well fed state decreases its activity by increases its activity by phosphorylation (action of AMPk /cAMP-dependent protein kinase) Dephosphorylation (action of phosphatase)
- 29. They are used to decrease plasma cholesterol levels in patients with hypercholester olemia Statin drugs are structural analogs of HMG-CoA reversible competitive inhibitors of HMG Co A reductase Statins (Lovastatin, Mevastatin, Atorva Statin etc.
- 30. 2.Long Term Regulation (gene regulation) Repression of HMG-CoA reductase gene (Controlled by the sterol regulatory element binding protein (SREBP) modulating its expression) Cholesterol (uptake by cells)