The roles of gap junctional intercellular communication in non-alcoholic steatohepatitis (NASH) and liver fibrosis

Abstract

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.