调脂领域新纪元ppt课件.pptVIP

来源于饮食或胆汁的胆固醇进入肠道，在肠腔内被胆汁酸乳化形成混合脂质微团（胆固醇微团）。微团将脂质由肠腔运送至粘膜表面，并在此被肠道细胞所吸收。一旦进入上皮细胞，游离胆固醇即被乙酰辅酶A：胆固醇酰基转移酶（ACAT）酯化，并装配形成乳糜微粒 (CMs)，乳糜微粒被分泌入淋巴，继而进入血液。 降胆固醇药物可作用于这个过程中的多个环节。树脂类药物提高粪便胆汁酸的排泄，而植物固醇（plant stanols）则干扰胆固醇微团的形成。迄今为止，医学界对胆固醇向肠上皮细胞的转运以及相关药物的作用机理尚未完全了解。目前认为NPC1L1(Niemann-Pick C1 Like 1)即胆固醇转运蛋白参与胆固醇从肠腔吸收进入肠粘膜上皮细胞的过程，因此NPC1L1抑制剂可在此环节阻断胆固醇的吸收。此外，业已证实，目前发现的ACAT抑制剂的临床疗效不尽理想。 Key Point: Ezetimibe is the first in the class of lipid-lowering drugs called cholesterol absorption inhibitors that have a unique mechanism of action, which complements that of statins. Additional Background Information: Ezetimibe localizes and appears to act at the brush border of the small intestine and inhibits the absorption of cholesterol from the intestinal lumen into enterocytes. Administration of ezetimibe results in: Decreased delivery of cholesterol from the intestine to the liver. Reduced hepatic cholesterol stores. Increased clearance of cholesterol from the blood. In a 2-week study of 18 hypercholesterolemic patients, ezetimibe inhibited 54% of all intestinal cholesterol absorption compared with placebo (P0.001).1 Reference: 1. Sudhop T, Lütjohann D, Kodal A, et al. Inhibition of intestinal cholesterol absorption by ezetimibe in humans. Circulation. 2002;106:1943–1948. To determine whether ezetimibe was selective for cholesterol, the absorption of radioactively labeled cholesterol and other steroids was measured in the presence of ezetimibe 0.3 mg/kg (cholesterol, progesterone, and ethinyl estradiol), ezetimibe 10 mg/kg (vitamin A, vitamin D, and taurocholic acid) or control vehicle. Ezetimibe significantly reduced cholesterol absorption (by 67%; P0.001), but it had no significant effect on absorption of any other steroid (progesterone, ethinyl estradiol, vitamin A, vitamin D, or taurocholic acid). van Heek M, Farley C, Compton DS, et al. Ezetimibe selectively inhibits intestinal cholesterol absorption in rodents in the presence and absence of exocrine pancreatic functi