Division of Endocrinology and Metabolism, Department of Medicine, Shiga University of Medical Science, Seta, Otsu, Shiga, Japan.
Am J Physiol Endocrinol Metab. 2013 Jul 15;305(2):E293-304. doi: 10.1152/ajpendo.00442.2012. Epub 2013 May 28.
Nonalcoholic fatty liver disease is the most frequent liver disease. Ezetimibe, an inhibitor of intestinal cholesterol absorption, has been reported to ameliorate hepatic steatosis in human and animal models. To explore how ezetimibe reduces hepatic steatosis, we investigated the effects of ezetimibe on the expression of lipogenic enzymes and intestinal lipid metabolism in mice fed a high-fat or a high-fructose diet. CBA/JN mice were fed a high-fat diet or a high-fructose diet for 8 wk with or without ezetimibe. High-fat diet induced hepatic steatosis accompanied by hyperinsulinemia. Treatment with ezetimibe reduced hepatic steatosis, insulin levels, and glucose production from pyruvate in mice fed the high-fat diet, suggesting a reduction of insulin resistance in the liver. In the intestinal analysis, ezetimibe reduced the expression of fatty acid transfer protein-4 and apoB-48 in mice fed the high-fat diet. However, treatment with ezetimibe did not prevent hepatic steatosis, hyperinsulinemia, and intestinal apoB-48 expression in mice fed the high-fructose diet. Ezetimibe decreased liver X receptor-α binding to the sterol regulatory element-binding protein-1c promoter but not expression of carbohydrate response element-binding protein and fatty acid synthase in mice fed the high-fructose diet, suggesting that ezetimibe did not reduce hepatic lipogenesis induced by the high-fructose diet. Elevation of hepatic and intestinal lipogenesis in mice fed a high-fructose diet may partly explain the differences in the effect of ezetimibe.
非酒精性脂肪性肝病是最常见的肝脏疾病。肠道胆固醇吸收抑制剂依折麦布已被报道可改善人类和动物模型的肝脂肪变性。为了探讨依折麦布如何减轻肝脂肪变性，我们研究了依折麦布对高脂肪或高果糖饮食喂养的小鼠肝脏中脂肪生成酶和肠道脂质代谢的影响。CBA/JN 小鼠用高脂肪饮食或高果糖饮食喂养 8 周，同时给予或不给予依折麦布。高脂肪饮食可诱导肝脂肪变性伴高胰岛素血症。依折麦布治疗可降低高脂肪饮食喂养的小鼠的肝脂肪变性、胰岛素水平和丙酮酸的葡萄糖生成，表明肝脏胰岛素抵抗降低。在肠道分析中，依折麦布降低了高脂肪饮食喂养的小鼠中脂肪酸转位蛋白-4 和 apoB-48 的表达。然而，依折麦布治疗并不能预防高果糖饮食喂养的小鼠的肝脂肪变性、高胰岛素血症和肠道 apoB-48 表达。依折麦布降低了肝脏 X 受体-α与固醇调节元件结合蛋白-1c 启动子的结合，但不降低碳水化合物反应元件结合蛋白和脂肪酸合酶在高果糖饮食喂养的小鼠中的表达，表明依折麦布不能减少高果糖饮食诱导的肝脂肪生成。高脂肪饮食喂养的小鼠肝脏和肠道脂肪生成的升高可能部分解释了依折麦布作用的差异。
