title: Ezetimibe increases hepatic iron levels in mice fed a high-fat diet.
abstract: 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.
authors.affiliation: Department of Clinical Laboratory Medicine, Kinki University Faculty of Medicine, 377-2, Ohnohigashi, Osakasayama 589-8511, Japan.
authors.forename: Yoshizumi
authors.initials: Y
authors.lastname: Kishino
authors.forename: Yuji
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Takanori
authors.initials: T
authors.lastname: Ikeda
authors.forename: Kazuo
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ogawa
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Iwatani
authors.forename: Toshinori
authors.initials: T
authors.lastname: Kamisako
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001384:Azetidines / Q000494:pharmacology*; D015415:Biomarkers; D001835:Body Weight / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism; D059305:Diet, High-Fat; D000069438:Ezetimibe; D005227:Fatty Acids / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D007501:Iron / Q000378:metabolism*; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis / Q000302:isolation & purification; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D000924:Anticholesteremic Agents; D001384:Azetidines; D015415:Biomarkers; D005227:Fatty Acids; D012333:RNA, Messenger; D002784:Cholesterol; D007501:Iron; D000069438:Ezetimibe