Naiki-Ito Aya
Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences.
Nihon Yakurigaku Zasshi. 2021;156(3):152-156. doi: 10.1254/fpj.20100.
Non-alcoholic steatohepatitis (NASH) is a common risk factor for fibrosis, cirrhosis, and a predisposing factor for the development of hepatocellular carcinoma. Recently, incidence of NASH has increased due to an increase in metabolic syndrome. Connexin (Cx)32, a hepatocyte gap-junction protein, plays an important role in liver tissue homeostasis; Cx32 dominant-negative transgenic rat (Cx32ΔTg) has much decreased gap-junctional intercellular communication, and high susceptibility to carcinogens. We found for the first time that Cx32 has play suppressive roles in inflammation and fibrosis of NASH using Cx32ΔTg received methionine-choline deficient diet (MCDD). Elevation of reactive oxygen species (ROS) play important roles in progression of NASH and elimination of ROS by antioxidant luteolin inhibited NASH in the Cx32ΔTg-MCDD model. This model had histological changes similar to those of human NASH, but was not accompanied by the metabolic syndrome such as obesity and insulin resistance. Therefore, we further established an improved NASH model. Cx32ΔTg rats and wild-type rats were fed a high-fat diet (HFD) and dimethylnitrosamine to induce NASH with metabolic syndrome. The HFD and DMN increased body, liver, and visceral fat weights in both genotypes. Serum insulin level and HOMA-IR score in Cx32ΔTg rats were higher than those in wild-type rats. Elevation of serum hepatic enzymes (AST, ALT), inflammatory cytokine expressions, α-smooth muscle actin expression, progression of steatohepatitis and fibrosis were induced by HFD and dimethylnitrosamine especially in Cx32ΔTg rats. These results indicate Cx32 dysfunction promoted the development of NASH and fibrosis accompanied by metabolic syndrome through accumulation of oxidative stress.
非酒精性脂肪性肝炎（NASH）是肝纤维化、肝硬化的常见危险因素，也是肝细胞癌发生的诱发因素。近年来，由于代谢综合征的增加，NASH的发病率有所上升。连接蛋白（Cx）32是一种肝细胞间隙连接蛋白，在肝组织稳态中起重要作用；Cx32显性负性转基因大鼠（Cx32ΔTg）的间隙连接细胞间通讯大幅减少，且对致癌物高度敏感。我们首次发现，使用接受蛋氨酸-胆碱缺乏饮食（MCDD）的Cx32ΔTg大鼠，Cx32在NASH的炎症和纤维化中发挥抑制作用。活性氧（ROS）的升高在NASH的进展中起重要作用，抗氧化剂木犀草素清除ROS可抑制Cx32ΔTg-MCDD模型中的NASH。该模型具有与人NASH相似的组织学变化，但不伴有肥胖和胰岛素抵抗等代谢综合征。因此，我们进一步建立了一种改良的NASH模型。给Cx32ΔTg大鼠和野生型大鼠喂食高脂饮食（HFD）并给予二甲基亚硝胺，以诱导伴有代谢综合征的NASH。HFD和DMN均增加了两种基因型大鼠的体重、肝脏和内脏脂肪重量。Cx32ΔTg大鼠的血清胰岛素水平和HOMA-IR评分高于野生型大鼠。HFD和二甲基亚硝胺尤其在Cx32ΔTg大鼠中诱导了血清肝酶（AST、ALT）升高、炎性细胞因子表达、α-平滑肌肌动蛋白表达、脂肪性肝炎和纤维化进展。这些结果表明，Cx32功能障碍通过氧化应激积累促进了伴有代谢综合征的NASH和纤维化的发展。
