Deletion of both p62 and Nrf2 spontaneously          results in the development of nonalcoholic steatohepatitis

Kentaro Akiyama; Eiji Warabi; Kosuke Okada; Toru Yanagawa; Tetsuro Ishii; Katsumi Kose; Katsutoshi Tokushige; Kazunori Ishige; Yuji Mizokami; Kenji Yamagata; Kojiro Onizawa; Shun-ichi Ariizumi; Masakazu Yamamoto; Junichi Shoda

doi:10.1538/expanim.17-0112

Original

Deletion of both p62 and Nrf2 spontaneously results in the development of nonalcoholic steatohepatitis

Kentaro Akiyama, Eiji Warabi, Kosuke Okada, Toru Yanagawa, Tetsuro Ishii, Katsumi Kose, Katsutoshi Tokushige, Kazunori Ishige, Yuji Mizokami, Kenji Yamagata, Kojiro Onizawa, Shun-ichi Ariizumi, Masakazu Yamamoto, Junichi Shoda

Author information

Kentaro Akiyama
Doctoral Programs in Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-shi, Ibaraki 305-8575, Japan
Japan Society for the Promotion of Science, 5-3-1 Kojimachi, Chiyoda-ku, Tokyo 102-0083, Japan
Eiji Warabi
Division of Biomedical Science, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-shi, Ibaraki 305-8575, Japan
Kosuke Okada
Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-shi, Ibaraki 305-8575, Japan
Toru Yanagawa
Division of Oral and Maxillofacial Surgery, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-shi, Ibaraki 305-8575, Japan
Tetsuro Ishii
Division of Biomedical Science, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-shi, Ibaraki 305-8575, Japan
Katsumi Kose
Institute of Applied Physics, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-shi, Ibaraki 305-8573, Japan
Katsutoshi Tokushige
Institute of Gastroenterology Internal Medicine, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
Kazunori Ishige
Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-shi, Ibaraki 305-8575, Japan
Yuji Mizokami
Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-shi, Ibaraki 305-8575, Japan
Kenji Yamagata
Division of Oral and Maxillofacial Surgery, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-shi, Ibaraki 305-8575, Japan
Kojiro Onizawa
Division of Oral and Maxillofacial Surgery, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-shi, Ibaraki 305-8575, Japan
Shun-ichi Ariizumi
Institute of Gastroenterology Surgery, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan
Masakazu Yamamoto
Institute of Gastroenterology Surgery, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan
Junichi Shoda
Medical Sciences, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-shi, Ibaraki 305-8575, Japan

Keywords: dysbiosis, hyperphagia, intestinal permeability, lipopolysaccharide, multiple parallel hits hypothesis

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Supplementary material

2018 Volume 67 Issue 2 Pages 201-218

DOI https://doi.org/10.1538/expanim.17-0112

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Abstract

Nonalcoholic steatohepatitis (NASH) is one of the leading causes of chronic liver disease worldwide. However, details of pathogenetic mechanisms remain unknown. Deletion of both p62/Sqstm1 and Nrf2 genes spontaneously led to the development of NASH in mice fed a normal chow and was associated with liver tumorigenesis. The pathogenetic mechanism (s) underlying the NASH development was investigated in p62:Nrf2 double-knockout (DKO) mice. DKO mice showed massive hepatomegaly and steatohepatitis with fat accumulation and had hyperphagia-induced obesity coupled with insulin resistance and adipokine imbalance. They also showed dysbiosis associated with an increased proportion of gram-negative bacteria species and an increased lipopolysaccharide (LPS) level in feces. Intestinal permeability was elevated in association with both epithelial damage and decreased expression levels of tight junction protein zona occludens-1, and thereby LPS levels were increased in serum. For Kupffer cells, the foreign body phagocytic capacity was decreased in magnetic resonance imaging, and the proportion of M1 cells was increased in DKO mice. In vitro experiments showed that the inflammatory response was accelerated in the p62:Nrf2 double-deficient Kupffer cells when challenged with a low dose of LPS. Diet restriction improved the hepatic conditions of NASH in association with improved dysbiosis and decreased LPS levels. The results suggest that in DKO mice, activation of innate immunity by excessive LPS flux from the intestines, occurring both within and outside the liver, is central to the development of hepatic damage in the form of NASH.

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