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Research ArticleMetabolism, Transport, and Pharmacogenomics

Ezetimibe Increases Hepatic Iron Levels in Mice Fed a High-Fat Diet

Yoshizumi Kishino, Yuji Tanaka, Takanori Ikeda, Kazuo Yamamoto, Hiroshi Ogawa, Yoshinori Iwatani and Toshinori Kamisako
Journal of Pharmacology and Experimental Therapeutics June 2013, 345 (3) 483-491; DOI: https://doi.org/10.1124/jpet.113.203448
Yoshizumi Kishino
Department of Clinical Laboratory Medicine, Kinki University Faculty of Medicine, Osakasayama (Y.K., Y.T., T.K.); Department of Biomedical Informatics, Division of Health Sciences, Osaka University Graduate School of Medicine, Suita (Y.K., Y.I.); Faculty of Human Sciences, Tezukayama Gakuin University, Sakai (T.I., H.O.); and Division of Basic Medical Science, Kinki University Faculty of Medicine, Osakasayama, Osaka, Japan (K.Y.)
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Yuji Tanaka
Department of Clinical Laboratory Medicine, Kinki University Faculty of Medicine, Osakasayama (Y.K., Y.T., T.K.); Department of Biomedical Informatics, Division of Health Sciences, Osaka University Graduate School of Medicine, Suita (Y.K., Y.I.); Faculty of Human Sciences, Tezukayama Gakuin University, Sakai (T.I., H.O.); and Division of Basic Medical Science, Kinki University Faculty of Medicine, Osakasayama, Osaka, Japan (K.Y.)
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Takanori Ikeda
Department of Clinical Laboratory Medicine, Kinki University Faculty of Medicine, Osakasayama (Y.K., Y.T., T.K.); Department of Biomedical Informatics, Division of Health Sciences, Osaka University Graduate School of Medicine, Suita (Y.K., Y.I.); Faculty of Human Sciences, Tezukayama Gakuin University, Sakai (T.I., H.O.); and Division of Basic Medical Science, Kinki University Faculty of Medicine, Osakasayama, Osaka, Japan (K.Y.)
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Kazuo Yamamoto
Department of Clinical Laboratory Medicine, Kinki University Faculty of Medicine, Osakasayama (Y.K., Y.T., T.K.); Department of Biomedical Informatics, Division of Health Sciences, Osaka University Graduate School of Medicine, Suita (Y.K., Y.I.); Faculty of Human Sciences, Tezukayama Gakuin University, Sakai (T.I., H.O.); and Division of Basic Medical Science, Kinki University Faculty of Medicine, Osakasayama, Osaka, Japan (K.Y.)
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Hiroshi Ogawa
Department of Clinical Laboratory Medicine, Kinki University Faculty of Medicine, Osakasayama (Y.K., Y.T., T.K.); Department of Biomedical Informatics, Division of Health Sciences, Osaka University Graduate School of Medicine, Suita (Y.K., Y.I.); Faculty of Human Sciences, Tezukayama Gakuin University, Sakai (T.I., H.O.); and Division of Basic Medical Science, Kinki University Faculty of Medicine, Osakasayama, Osaka, Japan (K.Y.)
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Yoshinori Iwatani
Department of Clinical Laboratory Medicine, Kinki University Faculty of Medicine, Osakasayama (Y.K., Y.T., T.K.); Department of Biomedical Informatics, Division of Health Sciences, Osaka University Graduate School of Medicine, Suita (Y.K., Y.I.); Faculty of Human Sciences, Tezukayama Gakuin University, Sakai (T.I., H.O.); and Division of Basic Medical Science, Kinki University Faculty of Medicine, Osakasayama, Osaka, Japan (K.Y.)
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Toshinori Kamisako
Department of Clinical Laboratory Medicine, Kinki University Faculty of Medicine, Osakasayama (Y.K., Y.T., T.K.); Department of Biomedical Informatics, Division of Health Sciences, Osaka University Graduate School of Medicine, Suita (Y.K., Y.I.); Faculty of Human Sciences, Tezukayama Gakuin University, Sakai (T.I., H.O.); and Division of Basic Medical Science, Kinki University Faculty of Medicine, Osakasayama, Osaka, Japan (K.Y.)
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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.

Footnotes

    • Received January 23, 2013.
    • Accepted March 27, 2013.
  • This work was supported by JSPS Kakenhi [Grants 23580188 and 24501010].

  • dx.doi.org/10.1124/jpet.113.203448.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 345 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 345, Issue 3
1 Jun 2013
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Research ArticleMetabolism, Transport, and Pharmacogenomics

Effects of Ezetimibe on Iron Metabolism

Yoshizumi Kishino, Yuji Tanaka, Takanori Ikeda, Kazuo Yamamoto, Hiroshi Ogawa, Yoshinori Iwatani and Toshinori Kamisako
Journal of Pharmacology and Experimental Therapeutics June 1, 2013, 345 (3) 483-491; DOI: https://doi.org/10.1124/jpet.113.203448

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Research ArticleMetabolism, Transport, and Pharmacogenomics

Effects of Ezetimibe on Iron Metabolism

Yoshizumi Kishino, Yuji Tanaka, Takanori Ikeda, Kazuo Yamamoto, Hiroshi Ogawa, Yoshinori Iwatani and Toshinori Kamisako
Journal of Pharmacology and Experimental Therapeutics June 1, 2013, 345 (3) 483-491; DOI: https://doi.org/10.1124/jpet.113.203448
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