![– 7 yo admitted w/ MI symptoms
• [TC] = 1240 mg/dl
• [TG] = 350 mg/dl
• [TC]father = 355 mg/dl
• [TC]mother = 310 mg/dl](https://image.slidesharecdn.com/cholesterolmetabolism-140307082857-phpapp02/75/Cholesterol-metabolism-38-2048.jpg)
![– 2 wks after MI had coronary bypass surgery
– Past year severe angina & second bypass
– Despite low-fat diet, cholestyramine, &
lovastatin, [TC] = 1000 mg/dl](https://image.slidesharecdn.com/cholesterolmetabolism-140307082857-phpapp02/75/Cholesterol-metabolism-39-2048.jpg)
Uploaded byDr Muhammad Mustansar
Cholesterol metabolism
The document discusses cholesterol and lipid metabolism. It notes that cholesterol is a membrane component and precursor to bile acids, vitamin D, and steroid hormones. The liver plays a central role in cholesterol balance, receiving cholesterol from the diet, other tissues, and through de novo synthesis. The liver exports cholesterol via VLDL and excretes it into bile. De novo synthesis occurs primarily in the liver through a multi-step process. Cholesterol synthesis is regulated by feedback from cellular cholesterol levels and covalent modification of HMG-CoA reductase. Bile acids are the major excretory form of cholesterol and aid in lipid digestion.
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Cholesterol metabolism
- 2. Cholesterol And SterolMetabolism DR MUHAMMAD MUSTANSAR
- 3.
- 4. Cholesterol Functions • Membranecomponent • Precurser to – Bile acids – Vitamin D – Steroid hormones
- 5. Central Role ofthe liver in Cholesterol Balance: Sources of hepatic cholesterol • Dietary cholesterol – From chylomicron remnants • Cholesterol from extra-hepatic tissues – Reverse cholesterol transport via HDL • Chylomicron remnants • IDL • De novo synthesis
- 7. Central Role ofthe liver in Cholesterol Balance: Fate of hepatic cholesterol • VLDL -> LDL – Transport to extra-hepatic tissues • Direct excretion into bile – Gallstones commonly are precipitates of cholesterol • Occurs when bile becomes supersaturated with cholesterol – Obesity, biliary stasis, infections • Bile acid synthesis and excretion into bile
- 8. De novo Synthesisof Cholesterol • Primary site: liver (~1g/d) – Secondary sites: adrenal cortex, ovaries, testes • Overall equation:
- 10. Hydroxymethylglutaryl-coenzyme A (HMG-CoA) isthe precursor for cholesterol synthesis. HMG-CoA is also an intermediate on the pathway for synthesis of ketone bodies from acetyl-CoA. The enzymes for ketone body production are located in the mitochondrial matrix. HMG-CoA destined for cholesterol synthesis is made by equivalent, but different, enzymes in the cytosol.
- 12. HMG-CoA isformed by condensation of acetyl-CoA & acetoacetyl-CoA, catalyzed by HMG-CoA Synthase. HMG-CoA Reductase catalyzes production of mevalonate from HMG-CoA.
- 13. De novo Synthesisof Cholesterol: four stages • Formation of HMG CoA (cyto) – Analogous to KB synthesis (mito) • Conversion of HMG CoA to activated isoprenoids
- 15. De novo Synthesisof Cholesterol: four stages • Condensation of isoprenoids to squalene – Six isoprenoids condense to form 30-C molecue
- 17. De novo synthesisof Cholesterol: four stages • Conversion of Squalene to Cholesterol
- 18. De novo Synthesisof Cholesterol: What do you need to know? • All carbons from acetyl-CoA • Requires NADPH, ATP, & O2 • Stages – One: forms HMG CoA – Two: forms activated 5 carbon intermediates (isoprenoids) – Three: six isoprenoids form squalene – Four: squalene + O2 form cholesterol
- 20. Regulation of Cholesterol Synthesis •Cellular cholesterol content exerts transcriptional control – HMG-CoA reductase • Half life = 2 hours – LDL-receptor synthesis • Nutrigenomics: – interactions between environment and individual genes and how these interactions affect clinical outcomes
- 21. Regulation of Cholesterol Synthesis •Covalent Modification of HMG-CoA Reductase – Insulin induces protein phosphatase – Activates HMG-CoA reductase • Feeding promotes cholesterol synthesis – Activates reg. enzyme – Provides substrate: acetyl CoA – Provides NADPH
- 23. Regulation of CholesterolSynthesis • Covalent Modification of HMG-CoA Reductase – Glucagon stimulates adenyl cyclase producing cAMP – cAMP activates protein kinase A – Inactivates HMG-CoA reductase • Fasting inhibits cholesterol synthesis
- 25. Cholesterol and BileAcid / Salt Metabolism • Major excretory form of cholesterol – Steroid ring is not degraded in humans – Occurs in liver • Bile acid/salts involved in dietary lipid digestion as emulsifiers
- 27. Types of BileAcids / Salts • Primary bile acids – Good emulsifying agents • All OH groups on same side • pKa = 6 (partially ionized) • Conjugated bile salts – Amide bonds with glycine or taurine – Very good emulsifier • pKa lower than bile acids
- 29. Synthesis of BileSalts • Hydroxylation – Cytochrome P-450/mixed function oxidase system • Side chain cleavage • Conjugation
- 30. • Secondary bileacids – Intestinal bacterial modification • Deconjugation • Dehydroxylation – Deoxycholic acid – Lithocholic acid
- 32. Recycling of BileAcids • Enterohepatic circulation – 98% recycling of bile acids • Cholestyramine Treatment – Resin binds bile acids – Prevents recycling – Increased uptake of LDL-C for bile acid synthesis
- 34. Plant stanols No doublebond on B ring Plant sterols Different side chains
- 35.
- 36. Statin drugs arestructural analogs of HMG-CoA
- 37. Case Study -familial hypercholesterolemia •8 yo girl – Admitted for heart/liver transplant • History – CHD in family – 2 yo xanthomas appear on legs – 4 yo xanthomas appear on elbows
- 38. – 7 yoadmitted w/ MI symptoms • [TC] = 1240 mg/dl • [TG] = 350 mg/dl • [TC]father = 355 mg/dl • [TC]mother = 310 mg/dl
- 39. – 2 wksafter MI had coronary bypass surgery – Past year severe angina & second bypass – Despite low-fat diet, cholestyramine, & lovastatin, [TC] = 1000 mg/dl
- 40. Xanthomas • Raised, waxyappearing, often yellow skin lesions (shown here on knee) – Associated with hyperlipidemia • Tendon xanthomas common on Achilles and hand extensor tendons
- 41. Xanthomas Raised lesions relatedto hyperlipidemia Eruptive Xanthomas -generally associated with hypertriglyceridemia Xanthomas of the eyelid -generally associated with hypercholesterolemia
- 42. Did Da Vinci’s MonaLisa have hyper-cholesterolemia ?
- 43. Steroid Hormone Metabolism: AdrenalSteroid Hormones • Aldosterone – C21 derivative of cholesterol – Promotes renal • Sodium retention • Potassium excretion
- 44. • Glucocorticoids (cortisol) –Starvation • Hepatic gluconeogenesis • Muscle protein degradation • Adipose lipolysis • Adrenal androgens – Dehydroepiandroterone (DHEA) • Precurser to potent androgens in extra-adrenal tissues