Molecular Structure and Function, Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, Canada.
Am J Physiol Gastrointest Liver Physiol. 2012 May 1;302(9):G1043-52. doi: 10.1152/ajpgi.00250.2011. Epub 2012 Feb 16.
Ezetimibe is a cholesterol uptake inhibitor that targets the Niemann-Pick C1-like 1 cholesterol transporter. Ezetimibe treatment has been shown to cause significant decreases in plasma cholesterol levels in patients with hypercholesterolemia and familial hypercholesterolemia. A recent study in humans has shown that ezetimibe can decrease the release of atherogenic postprandial intestinal lipoproteins. In the present study, we evaluated the mechanisms by which ezetimibe treatment can lower postprandial apoB48-containing chylomicron particles, using a hyperlipidemic and insulin-resistant hamster model fed a diet rich in fructose and fat (the FF diet) and fructose, fat, and cholesterol (the FFC diet). Male Syrian Golden hamsters were fed either chow or the FF or FFC diet ± ezetimibe for 2 wk. After 2 wk, chylomicron production was assessed following intravenous triton infusion. Tissues were then collected and analyzed for protein and mRNA content. FFC-fed hamsters treated with ezetimibe showed improved glucose tolerance, decreased fasting insulin levels, and markedly reduced circulating levels of TG and cholesterol in both the LDL and VLDL fractions. Examination of triglyceride (TG)-rich lipoprotein (TRL) fractions showed that ezetimibe treatment reduced postprandial cholesterol content in TRL lipoproteins as well as reducing apoB48 content. Although ezetimibe did not decrease TRL-TG levels in FFC hamsters, ezetimibe treatment in FF hamsters resulted in decreases in TRL-TG. Jejunal apoB48 protein expression was lower in ezetimibe-treated hamsters. Reductions in jejunal protein levels of scavenger receptor type B-1 (SRB-1) and fatty acid transport protein 4 were also observed. In addition, ezetimibe-treated hamsters showed significantly lower jejunal mRNA expression of a number of genes involved in lipid synthesis and transport, including srebp-1c, sr-b1, ppar-γ, and abcg1. These data suggest that treatment with ezetimibe not only inhibits cholesterol uptake, but may also alter intestinal function to promote improved handling of dietary lipids and reduced chylomicron production. These, in turn, promote decreases in fasting and postprandial lipid levels and improvements in glucose homeostasis.
依泽替米贝是一种胆固醇摄取抑制剂，作用靶点为 Niemann-Pick C1 样 1 胆固醇转运蛋白。研究表明，依泽替米贝可显著降低高胆固醇血症和家族性高胆固醇血症患者的血浆胆固醇水平。最近一项人类研究显示，依泽替米贝可降低餐后致动脉粥样硬化性肠道脂蛋白的释放。本研究通过高脂血症和胰岛素抵抗金黄仓鼠模型（喂食富含果糖和脂肪的饮食[FF 饮食]以及果糖、脂肪和胆固醇[FFC 饮食]），评估了依泽替米贝降低餐后载脂蛋白 B48 富含乳糜微粒颗粒的机制。雄性金黄仓鼠喂食标准饲料或 FF 或 FFC 饮食+/-依泽替米贝 2 周。2 周后，经静脉推注 Triton 评估乳糜微粒生成。然后收集组织并分析蛋白和 mRNA 含量。与 FFC 饮食组相比，FFC 饮食+依泽替米贝组仓鼠的葡萄糖耐量改善，空腹胰岛素水平降低，LDL 和 VLDL 两部分的 TG 和胆固醇循环水平显著降低。对富含甘油三酯的脂蛋白（TRL）进行检查显示，依泽替米贝治疗可降低 TRL 脂蛋白中的餐后胆固醇含量和载脂蛋白 B48 含量。尽管依泽替米贝未降低 FFC 饮食组仓鼠的 TRL-TG 水平，但在 FF 饮食组仓鼠中，TRL-TG 水平降低。依泽替米贝治疗组仓鼠的空肠载脂蛋白 B48 蛋白表达降低。还观察到清道夫受体 B-1（SRB-1）和脂肪酸转运蛋白 4 的空肠蛋白水平降低。此外，依泽替米贝治疗组仓鼠的一些涉及脂质合成和转运的基因的空肠 mRNA 表达明显降低，包括 srebp-1c、sr-b1、ppar-γ 和 abcg1。这些数据表明，依泽替米贝治疗不仅抑制胆固醇摄取，还可能改变肠道功能，促进膳食脂质的更好处理和乳糜微粒生成减少。这反过来又促进空腹和餐后脂质水平降低以及葡萄糖稳态改善。
