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Gender difference in development of steatohepatitis in <i>p62/Sqstm1 and Nrf2</i> double-knockout mice

  • WATAHIKI Takahisa
    Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-shi, Ibaraki 305-8575, Japan
  • OKADA Kosuke
    Tsukuba Preventive Medicine Research Center, University of Tsukuba Hospital, 1-1-1 Tennodai, Tsukuba-shi, Ibaraki 305-8575, Japan Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-shi, Ibaraki 305-8575, Japan
  • WARABI Eiji
    Division of Biomedical Sciences, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-shi, Ibaraki 305-8575, Japan
  • NAGAOKA Tsugumi
    Division of Medical Sciences, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-shi, Ibaraki 305-8575, Japan
  • SUZUKI Hideo
    Tsukuba Preventive Medicine Research Center, University of Tsukuba Hospital, 1-1-1 Tennodai, Tsukuba-shi, Ibaraki 305-8575, Japan Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-shi, Ibaraki 305-8575, Japan
  • ISHIGE Kazunori
    Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-shi, Ibaraki 305-8575, Japan
  • YANAGAWA Toru
    Department of Oral and Maxillofacial Surgery, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-shi, Ibaraki 305-8575, Japan
  • TAKAHASHI Satoru
    Division of Biomedical Sciences, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-shi, Ibaraki 305-8575, Japan
  • MIZOKAMI Yuji
    Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-shi, Ibaraki 305-8575, Japan
  • TOKUSHIGE Katsutoshi
    Institute of Gastroenterology and Internal Medicine, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
  • ARIIZUMI Shun-ichi
    Department of Surgery, Institute of Gastroenterology, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
  • YAMAMOTO Masakazu
    Department of Surgery, Institute of Gastroenterology, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
  • SHODA Junichi
    Division of Medical Sciences, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-shi, Ibaraki 305-8575, Japan

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Abstract

<p> Gender and menopause influence the severity and development manner of nonalcoholic steatohepatitis (NASH). Male p62/Sqstm1 and nuclear factor E2-related factor-2 (p62 and Nrf2) double-knockout (DKO) mice exhibit severe steatohepatitis caused by hyperphagia-induced obesity, overload of lipopolysaccharide (LPS) into the liver, and potentiation of the inflammatory response in Kupffer cells. However, the pathogenetic phenotype of steatohepatitis in female DKO mice remains unknown. Phenotypic changes of steatohepatitis in DKO mice were compared in terms of gender differences. Compared with DKO male mice, DKO female mice exhibited later onset of steatohepatitis with obesity after 30 weeks of age, as well as milder severity of hepatic inflammation and fibrosis. Serum estradiol was higher in female than male mice, with levels increasing up to 30 weeks of age before decreasing until 50 weeks of age (corresponding to the post-menopausal period). Fecal and serum LPS were lower in female mice than male mice, and inflammatory signaling in the liver was attenuated in female compared with male mice. Correlating with LPS levels, the composition of intestinal microbiota in female mice was different from male mice. Gender differences were observed for the development of steatohepatitis in DKO mice. Low-grade inflammatory hit in the liver under in vivo conditions of high estradiol may be attributable to the milder pathological features of steatohepatitis in female mice.</p>

Journal

  • Experimental Animals

    Experimental Animals 69 (4), 395-406, 2020

    Japanese Association for Laboratory Animal Science

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