Ezetimibe Increases Hepatic Iron Levels in Mice Fed a High-Fat Diet
Ezetimibe Increases Hepatic Iron Levels in Mice Fed a High-Fat Diet
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DOI：
10.1124/jpet.113.203448
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发表时间：
2013-06-01
影响因子：
3.5
通讯作者：
Kamisako, Toshinori
中科院分区：
文献类型：
--
作者：
Kishino, Yoshizumi;Tanaka, Yuji;Kamisako, Toshinori
越来越多的证据表明，依折麦布可能是治疗非酒精性脂肪肝病和脂肪性肝炎（NAFLD/NASH）的有前途的药物。放血和饮食铁限制可降低 NAFLD/NASH 患者的血清转氨酶。最近的研究表明，脂质代谢和铁代谢之间存在相互作用。因此，我们研究了依折麦布对饲喂含铁或不含铁的高脂肪饮食的小鼠铁代谢的影响。我们用以下饮食喂养 C57BL/6 小鼠 12 周。实验 1 包括 [1] 对照饮食 (C)、[2] C 加依折麦布（0.3 毫克/天；4 周）(CE)、[3] 高脂肪饮食 (H) 和 [4] H 加依折麦布 (HE)。实验2包括[1]含有羰基铁的C（平均；22.4毫克/天；6周）（CI）、[2]CI加依折麦布（CIE）、[3]含有羰基铁的H（HI）和[4]HI加依折麦布（HIE）。 12周后取出血液、肝脏和十二指肠。在实验1中，HE组的肝铁水平高于H组，而C组和CE组之间没有差异。肝脏转铁蛋白受体1和2、铁蛋白和铁调素的mRNA表达在CE中比C中增加更多，在HE中比H中增加更多。在十二指肠中，与C相比，CE中二价金属转运蛋白1、铁蛋白H和铁调素mRNA水平增加。在实验2中，HIE中的肝铁浓度高于HI。与 HI 相比，HIE 中肝脏铁蛋白 L 和铁调素 mRNA 表达增加。在十二指肠中，与 CIE 相比，HIE 中铁蛋白 L mRNA 增加。依折麦布诱导高脂饮食小鼠的肝铁摄取转运蛋白表达，导致肝铁浓度增加。
Accumulating evidence suggests that ezetimibe may be a promising agent for treatment of nonalcoholic fatty liver disease and steatohepatitis (NAFLD/NASH). Phlebotomy and dietary iron restriction reduce serum transaminase in NAFLD/NASH patients. Recent studies have shown that a mutual effect exists between lipid metabolism and iron metabolism. Accordingly, we examined the effect of ezetimibe on iron metabolism in mice fed a high-fat diet with or without iron. We fed C57BL/6 mice the following diets for 12 weeks. Experiment 1 comprised [1] a control diet (C), [2] C plus ezetimibe (0.3 mg/day; 4 weeks) (CE), [3] a high-fat diet (H), and [4] H plus ezetimibe (HE). Experiment 2 comprised [1] C containing carbonyl iron (average; 22.4 mg/day; 6 weeks) (CI), [2] CI plus ezetimibe (CIE), [3] H containing carbonyl iron (HI), and [4] HI plus ezetimibe (HIE). Blood, livers, and duodenum were removed after 12 weeks. In experiment 1, the hepatic iron levels were higher in HE than H, whereas there was no difference between C and CE. Hepatic mRNA expression of transferrin receptor 1 and 2, ferritins, and hepcidin were increased more in CE than C, and more in HE than H. In the duodenum, divalent metal transporter 1, ferritin H, and hephaestin mRNA levels were increased in CE compared with C. In experiment 2, hepatic iron concentrations were higher in HIE than HI. Hepatic mRNA expression of ferritin L and hepcidin were increased in HIE compared with HI. In duodenum, ferritin L mRNA was increased in HIE compared with CIE. Ezetimibe induced hepatic iron uptake transporter expression in mice fed a high-fat diet, causing increased hepatic iron concentrations.