cholesterol.ppt

1、Cholesterol Metabolism,Sources of cholesterol Cholesterol synthesis Long and short term regulation SREBP-2 Lowering cholesterol Calculating your risk for CHD,Roles of Cholesterol,Membrane component Steroid synthesis Bile acid/salt precursor Vitamin D precursor,Sources of Cholesterol,Diet,De novo syn

2、thesis,Cholesterol synthesized in extrahepatic tissues,Liver cholesterol pool,Free cholesterol In bile,Conversion to bile salts/acids,Secretion of HDL and VLDL,Cholesterol Structure,FA for esterification,Dietary Cholesterol,Animal products eggs Absorb about 50% Increase intake = decreased absorption

3、 Excrete 1 g/day (bile acids),Dietary Cholesterol,Assume 400 mg intake / day 200 mg is absorbed 1000 mg is excreted 800 mg from de novo synthesis Lowering cholesterol in diet has very little effect on blood cholesterol !,Cholesterol Synthesis,Similar to ketogenic pathway Occurs in cytosol Requires N

4、ADPH and ATP Highly regulated 80 % in liver, 10% intestine, 5% skin,Cholesterol Synthesis,HMG CoA Reductase : Regulation,Short-term regulation Inhibited by phosphorylation AMP-dependent protein kinase When AMP is high (or ATP low!), why waste energy on cholesterol synthesis Long-term regulation Prot

5、eolysis Degradation stimulated by cholesterol and cholesterol metabolites Sterol-sensing domain,HMG CoA reductase - Phosphorylation,AMP-Activated Protein Kinase (high activity),AMP-Activated Protein Kinase (low activity),phosphatase,insulin,(+),kinase,Glucagon/epi,(+),increase cAMP,AMP,(+),HMG CoA r

6、eductase OH (active),HMG CoA reductase P (inactive),Transcriptional regulation SREBP-2 Responds to cellular levels of sterols,HMG CoA Reductase : Regulation,SREBP cleavage activating protein,Site 1 and site 2 protease -,Free Cholesterol Pool,synthesis,Negative Feedback (-),LDL receptor,LP,Negative F

7、eedback (-),acat,CE,HDL,Steroid synthesis,C,Lowering Cholesterol,Statins decrease HMG CoA reductase activity Muscle weakness Why?,Bile sequestering agents,Lowering Cholesterol,Bile acids,liver,Bile acids,95 % reabsorbed,5% in feces,Bind bile acid Utilize more cholesterol to make bile acids,10% in feces,Lowering Cholesterol,Oat bran Soluble fiber Bind bile acids? Niacin 3-8 grams / day (need 60 mg) Inh