Nicotinic alpha-7 acetylcholine receptor deficiency exacerbates hepatic inflammation and fibrosis in a mouse model of non-alcoholic steatohepatitis

Aims/Introduction Non-alcoholic steatohepatitis (NASH), which occurs in association with insulin resistance and hepatic fat accumulation, is characterized by chronic liver injury and fibrosis. NASH onset and progression is closely related to hepatic inflammation, which is partly regulated by the vagus nerve through the alpha 7 nicotinic acetylcholine receptor (alpha 7nAchR). Hepatic alpha 7nAchR action is impeded in obesity and insulin resistance. In the present study, using alpha 7nAchR knockout (alpha 7KO) mice, we elucidated the effect of alpha 7nAchR deficiency on NASH-related inflammation and fibrosis. Materials and Methods alpha 7KO mice were fed an atherogenic high-fat diet (AD) for 32 weeks or methionine/choline-deficient diet (MCD) for 6 weeks, both of which induce NASH. Mice were then examined for the degree of NASH-related inflammation and fibrosis by hepatic gene expression analysis and Sirius red histological staining. Results Hepatic triglyceride accumulation and elevated plasma transaminase levels were observed in both AD and MCD mice, but the plasma transaminase level increase was higher in alpha 7KO mice than in control mice. alpha 7KO mice fed an AD showed significant upregulation of the Col1a1 gene encoding alpha-1 type I collagen, which is involved in liver fibrosis, and the Ccl2 gene encoding C-C motif chemokine ligand 2, a pro-inflammatory chemokine; alpha 7KO mice fed an MCD had significant upregulation of the Col1a1 gene and the Tnf gene, an inflammatory cytokine. Histological analysis showed that AD and MCD exacerbated liver fibrosis in alpha 7KO mice. Conclusions The results of this study suggest that alpha 7nAchR deficiency exacerbates hepatic inflammation and fibrosis in a diet-induced mouse model of NASH.