Estrogen receptor ligands ameliorate fatty liver through a nonclassical estrogen receptor/Liver X receptor pathway in mice

Authors

  • Song-iee Han,

    1. Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan
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  • Yoko Komatsu,

    1. Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan
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  • Akiko Murayama,

    1. Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan
    2. Center for Tsukuba Advanced Research Alliance (TARA), Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan
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  • Knut R. Steffensen,

    1. Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
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  • Yoshimi Nakagawa,

    1. Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
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  • Yuka Nakajima,

    1. Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan
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  • Michiko Suzuki,

    1. Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan
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  • Shohei Oie,

    1. Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan
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  • Paolo Parini,

    1. Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
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  • Lise-Lotte Vedin,

    1. Center for Biosciences, Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
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  • Hiroyuki Kishimoto,

    1. Center for Tsukuba Advanced Research Alliance (TARA), Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan
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  • Hitoshi Shimano,

    1. Center for Tsukuba Advanced Research Alliance (TARA), Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan
    2. Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
    3. International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Ibaraki, Japan
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  • Jan-Åke Gustafsson,

    1. Center for Biosciences, Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
    2. Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX
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  • Junn Yanagisawa

    Corresponding author
    1. Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan
    2. Center for Tsukuba Advanced Research Alliance (TARA), Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan
    • Address reprint requests to: Junn Yanagisawa, Ph.D., Graduate School of Life and Environmental Sciences, and Center for Tsukuba Advanced Research Alliance (TARA), Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan. E-mail: junny@agbi.tsukuba.ac.jp; fax: +81-29-853-7322.

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  • Potential conflict of interest: Nothing to report.

  • This work was supported by the Research Fellowship (to S.H. and Y.K.) from the Japan Society for the Promotion of Science. J-A.G. was supported by the Swedish Cancer Society, the Texas Emerging Technology Fund (under Agreement 18, no. 300-9-1958), and the Robert A. Welch Foundation (E-0004).

Abstract

Liver X receptor (LXR) activation stimulates triglyceride (TG) accumulation in the liver. Several lines of evidence indicate that estradiol-17β (E2) reduces TG levels in the liver; however, the molecular mechanism underlying the E2 effect remains unclear. Here, we show that administration of E2 attenuated sterol regulatory element-binding protein (SREBP)-1 expression and TG accumulation induced by LXR activation in mouse liver. In estrogen receptor alpha (ERα) knockout (KO) and liver-specific ERα KO mice, E2 did not affect SREBP-1 expression or TG levels. Molecular analysis revealed that ERα is recruited to the SREBP-1c promoter through direct binding to LXR and inhibits coactivator recruitment to LXR in an E2-dependent manner. Our findings demonstrate the existence of a novel liver-dependent mechanism controlling TG accumulation through the nonclassical ER/LXR pathway. To confirm that a nonclassical ER/LXR pathway regulates ERα-dependent inhibition of LXR activation, we screened ERα ligands that were able to repress LXR activation without enhancing ERα transcriptional activity, and, as a result, we identified the phytoestrogen, phloretin. In mice, phloretin showed no estrogenic activity; however, it did reduce SREBP-1 expression and TG levels in liver of mice fed a high-fat diet to an extent similar to that of E2. Conclusion: We propose that ER ligands reduce TG levels in the liver by inhibiting LXR activation through a nonclassical pathway. Our results also indicate that the effects of ER on TG accumulation can be distinguished from its estrogenic effects by a specific ER ligand. (Hepatology 2014;59:1791–1802)

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