PT  - JOURNAL ARTICLE
AU  - Yoshizumi Kishino
AU  - Yuji Tanaka
AU  - Takanori Ikeda
AU  - Kazuo Yamamoto
AU  - Hiroshi Ogawa
AU  - Yoshinori Iwatani
AU  - Toshinori Kamisako
TI  - Ezetimibe Increases Hepatic Iron Levels in Mice Fed a High-Fat Diet
AID  - 10.1124/jpet.113.203448
DP  - 2013 Jun 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 483--491
VI  - 345
IP  - 3
4099  - http://jpet.aspetjournals.org/content/345/3/483.short
4100  - http://jpet.aspetjournals.org/content/345/3/483.full
SO  - J Pharmacol Exp Ther2013 Jun 01; 345
AB  - 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.