谷固醇血症一种罕见的遗传性脂代谢紊乱课件（PPT 29页）.pptVIP

Sitosterolemia: A Rare Genetic Disorder Leads to Insight into an Important Physiological Process Evidence for Regulation of Dietary Cholesterol Absorption Interindividual variation in cholesterol absorption rates Absorption rates affected by dietary cholesterol levels High degree of specificity for sterol absorbed, e.g., cholesterol sitosterol Genetic disease in humans, phytosterolemia Cholesterol excreted into bile by the liver, but mechanism/transporters not identified How is Cholesterol Absorbed? Sterol Absorption Dietary Sterols: Normal Physiology Sterol Structures Sitosterolemia, a.k.a. Phytosterolemia Autosomal recessive, first described in 1974 Diagnostically elevated plasma phytosterols Rare, 1:1,000,000 (~20 cases in US) Associated with premature atherosclerosis Increased dietary sterol absorption and failure to excrete sterols into bile Need GC or HPLC to make diagnosis Sitosterolemia Biochemical abnormalities Increased plasma phytosterols and their metabolites Increased dietary cholesterol and plant sterol absorption Expanded body pools of both sitosterol and cholesterol Decreased ability to excrete any sterols into bile by the liver Plasma Sitosterol and Cholesterol in Sitosterolemia Summary of Metabolic Defect Loss of sterol discrimination, with Reduced bile excretion of sterols Hyperabsorption of all sterols Reduced sterol turnover Abnormal regulation of cholesterol synthetic pathway Reduced activities of HMG-CoA reductase, synthase, but increased LDL-receptor activity Sitosterol and Atherosclerosis:Insight from Homozygous Sitosterolemia Autopsy study of young sitosterolemic patient who had sudden death ~20% plant sterol content of atherosclerotic plaque Same proportions of sterols as in LDL Hypothesis Primary defect involves a gene product that Regulates cholesterol absorption in the gut Regulates cholesterol excretion in the liver Prevents noncholesterol sterols from being retained by the body Prevents entry in the intestine Any small