Department of Clinical Laboratory Medicine, Kinki University Faculty of Medicine, 377-2, Ohnohigashi, Osakasayama 589-8511, Japan.
J Pharmacol Exp Ther. 2013 Jun;345(3):483-91. doi: 10.1124/jpet.113.203448. Epub 2013 Mar 28.
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.
越来越多的证据表明，依折麦布可能是治疗非酒精性脂肪性肝病和脂肪性肝炎（NAFLD/NASH）的有前途的药物。放血和饮食中铁的限制可降低 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高脂饮食喂养的小鼠中铁代谢的影响，这些小鼠同时或不伴有铁。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 mg/天；4 周）（CE），[3]高脂饮食（H）和[4]H 加依折麦布（HE）。实验 2 包括[1]含羰基铁的 C（平均；22.4 mg/天；6 周）（CI），[2]CI 加依折麦布（CIE），[3]含羰基铁的 H（HI）和[4]H 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，与 H 相比，HE 组肝脏铁含量更高，而 C 与 CE 之间无差异。CE 组比 C 组转铁蛋白受体 1 和 2、铁蛋白和 hepcidin 的肝 mRNA 表达增加更多，HE 组比 H 组增加更多。在十二指肠中，与 C 相比，CE 组二价金属转运蛋白 1、铁蛋白 H 和 hephaestin 的 mRNA 水平升高。在实验 2 中，HIE 组肝脏铁浓度高于 HI 组。与 HI 相比，HIE 组肝脏铁蛋白 L 和 hepcidin 的 mRNA 表达增加。与 CIE 相比，HIE 组十二指肠铁蛋白 L 的 mRNA 表达增加。依折麦布诱导高脂饮食喂养的小鼠肝铁摄取转运体表达，导致肝铁浓度增加。
