A novel model of non-alcoholic steatohepatitis with fibrosis and carcinogenesis in connexin 32 dominant-negative transge
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ORGAN TOXICITY AND MECHANISMS
A novel model of non‑alcoholic steatohepatitis with fibrosis and carcinogenesis in connexin 32 dominant‑negative transgenic rats Aya Naiki‑Ito1 · Hiroyuki Kato1 · Taku Naiki1 · Ranchana Yeewa1 · Yoshinaga Aoyama1 · Yuko Nagayasu1 · Shugo Suzuki1,2 · Shingo Inaguma1 · Satoru Takahashi1 Received: 1 June 2020 / Accepted: 12 August 2020 © The Author(s) 2020
Abstract Non-alcoholic steatohepatitis (NASH) is a recognized risk factor for liver fibrosis and malignancies, and is associated with features of metabolic syndrome, such as obesity and insulin resistance (IR). We previously demonstrated that the disturbance of connexin 32 (Cx32), a gap junctional protein of hepatocytes, exacerbated NASH in Cx32 dominant-negative transgenic (Cx32ΔTg) rats fed methionine choline-deficient diet (MCDD). MCDD is well-established means of inducing NASH in rodents; however, the Cx32ΔTg-MCDD NASH model does not reproduce obesity and IR. In this study, we aimed to establish an improved NASH model. Eight-week-old male Cx32ΔTg and wild-type (Wt) rats received a high-fat diet (HFD) with dimethylnitrosamine (DMN) for 12 weeks. The HFD with DMN led to gains in body, liver, and visceral fat weights in both genotypes. IR was significantly greater in Cx32ΔTg than in Wt rats. Elevation of serum hepatic enzymes (AST, ALT), inflammatory cytokine expressions (Tnfα, Il-6, Tgf-β1, Il-1β, Timp2, and Col1a1), steatohepatitis, and fibrosis were significantly greater in Cx32ΔTg as compared with Wt rats. Regarding carcinogenesis, the number and area of glutathione S-transferase placental form (GST-P)-positive preneoplastic hepatic foci were significantly increased in Cx32ΔTg versus Wt rats. Moreover, activation of NF-κB and JNK contributed to the progression of NASH in Cx32ΔTg rats. These results suggest that Cx32 dysfunction promoted the progression of NASH, metabolic syndrome, and carcinogenesis. Therefore, the novel Cx32ΔTg–HFD–DMN NASH model may be a rapid and useful tool for evaluating the progression of NASH. Keywords NASH · Connexin · Insulin resistance · Fibrosis · Hepatocarcinogenesis Abbreviations ALT Alanine aminotransferase AST Aspartate aminotransferase Bex1 Brain expressed, X-linked 1 Ctrl Control Cx Connexin Cx32ΔTg Cx32 dominant-negative transgenic DMN Dimethylnitrosamine Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00204-020-02873-5) contains supplementary material, which is available to authorized users. * Aya Naiki‑Ito [email protected]‑cu.ac.jp 1
Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, 1‑Kawasumi, Mizuho‑cho, Mizuho‑ku, Nagoya 467‑8601, Japan
Department of Molecular Pathology, Osaka City University Graduate School of Medicine, Osaka, Japan
2
GST-P Glutathione S-transferase placental form HCC Hepatocellular carcinoma HFD High-fat diet HOMA-IR Homeostasis model assessment-insulin resistance HSC Hepatic stellate cells IR Insulin resistance MCDD Methionine c
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