Cholesterol And Sterol Metabolism胆固醇和胆固醇代谢.ppt

Cholesterol And Sterol Metabolism Cholesterol Functions Membrane component Precurser to Bile acids Vitamin D Steroid hormones Central Role of the 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 Central Role of the 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 De novo Synthesis of Cholesterol Primary site: liver (~1g/d) Secondary sites: adrenal cortex, ovaries, testes Overall equation: De novo Synthesis of Cholesterol:four stages Formation of HMG CoA (cyto) Analogous to KB synthesis (mito) Conversion of HMG CoA to activated isoprenoids De novo Synthesis of Cholesterol:four stages Condensation of isoprenoids to squalene Six isoprenoids condense to form 30-C molecue De novo Synthesis of Cholesterol:four stages Conversion of Squalene to Cholesterol De novo Synthesis of 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 Smith-Lemli-Opitz (SLO) syndrome(MAAG, chap 32, p 72) 3rd most common inborn error of metabolism in US Cystic fibrosis PKU 1/30 Americans of N. European descent are carriers (heterozygous advantage??) Prevalence of SLO is 1:20-60,000 Predicted prevalence: 1:5-18,000 Spontaneous abortion Underdiagnosed ? “multiple congenital abnormality syndrome of unknown aetiology” Deficiency of delta-7-dehydrocholesterol reductase 7-dehydrocholesterol -desmosterol - cholesterol Smith-Lemli-Opitz (SLO) syndrome multiple cong