Novel non‐alcoholic steatohepatitis model with histopathological and insulin‐resistant features |
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Authors: | Yohei Owada Takafumi Tamura Tomohito Tanoi Yusuke Ozawa Yoshio Shimizu Katsuji Hisakura Takashi Matsuzaka Hitoshi Shimano Noriyuki Nakano Shingo Sakashita Toshiya Matsukawa Hiroko Isoda Nobuhiro Ohkohchi |
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Affiliation: | 1. Department of Gastrointestinal and Hepato‐Biliary‐Pancreatic Surgery, Faculty of Medicine, University of Tsukuba, 1‐1‐1 Tennodai, Tsukuba 305‐8575, Japan;2. Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, 1‐1‐1 Tennodai, Tsukuba 305‐8575, Japan;3. International Institute for Integrative Sleep Medicine (WPI‐IIIS), University of Tsukuba, 1‐1‐1 Tennodai, Tsukuba 305‐8575, Japan;4. AMED‐CREST, Japan Agency for Medical Research and Development (AMED), Chiyoda‐ku, Tokyo, 100‐0004, Japan;5. Department of Diagnostic Pathology, Faculty of Medicine, University of Tsukuba, 1‐1‐1 Tennodai, Tsukuba 305‐8575, Japan;6. Graduate School of Environmental Sciences, University of Tsukuba, 1‐1‐1 Tennodai, Tsukuba 305‐8572, Japan |
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Abstract: | Although several non‐alcoholic steatohepatitis (NASH) models have been reported to date, few of these models fully reflect the histopathology and pathophysiology of human NASH. The aim of this study was to establish a novel NASH model by feeding a high‐fat (HF) diet and administering both carbon tetrachloride (CCl4) and the Liver X receptor agonist T0901317. Male C57BL/6J mice were divided into four groups (each n = 5): HF, HF + CCl4, HF + T0901317, and the novel NASH model (HF + CCl4 + T0901317). CCl4 (0.1 mL/kg) and T0901317 (2.5 mg/kg) were intraperitoneally administered four times and five times, respectively. The livers of the novel NASH model group presented a whitish colour. The serum levels of TNF‐α and IL‐6 were significantly increased in the novel NASH model group, and mice in this group exhibited histopathological features and insulin resistance reflective of NASH, i.e., macrovesicular hepatic steatosis, ballooning hepatocytes, Mallory‐Denk bodies, lobular inflammation and fibrosis. The novel NASH model group presented significantly upregulated expression levels of mRNAs related to lipogenesis, oxidative stress, fibrosis and steatosis and significantly downregulated expression levels of mRNAs related to triglyceride export. We successfully established a novel experimental NASH model that exhibits similar histopathology and pathophysiology to human NASH. |
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Keywords: | insulin resistance Liver X receptor mouse model NAFLD activity score non‐alcoholic steatohepatitis |
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