Hepatic vagus nerve regulates Kupffer cell activation via [alpha]7 nicotinic acetylcholine receptor in nonalcoholic steatohepatitis

Background Nonalcoholic fatty liver disease ranges from simple steatosis to nonalcoholic steatohepatitis (NASH). Kupffer cells play a central role in promoting hepatic inflammation, which leads to the development of NASH. We investigated the anti-inflammatory effect of hepatic vagus-mediated stimulation of the [alpha]7 nicotinic acetylcholine receptor ([alpha]7nAChR) on Kupffer cells in NASH pathogenesis. Methods Wild-type (WT) mice undergoing hepatic vagotomy (HV) were fed a methionine- and choline-deficient (MCD) diet for 1 week. [alpha]7nAChR knockout ([alpha]7KO) chimeric mice were generated by transplanting [alpha]7KO bone marrow cells into irradiated and Kupffer cell-deleted WT recipients. Kupffer cells were isolated from WT mice and treated with [alpha]7nAChR agonist under stimulation by lipopolysaccharide and/or palmitic acid. Results HV aggravated MCD diet-induced NASH in both steatosis and inflammation. The hepatic inflammatory response, including the upregulation of tumor necrosis factor alpha (TNF[alpha]), interleukin (IL)-12, and monocyte chemoattractant protein 1 (MCP-1), was accelerated in HV mice, accompanied by the downregulation of PPAR[alpha] pathway genes. Kupffer cells were highly activated via the phosphorylation and nuclear translocation of nuclear factor-kappa B (NF-[kappa]B) in MCD diet-fed HV mice. The [alpha]7nAchR agonist suppressed the inflammatory response of primary Kupffer cells induced by lipopolysaccharide and palmitic acid by attenuating the NF-[kappa]B cascade. [alpha]7KO chimeric mice fed an MCD diet for 1 week developed advanced NASH with highly activated Kupffer cells. The hepatic expression of TNF[alpha], IL-12, and MCP-1 was upregulated in [alpha]7KO chimeric mice, accompanied by abnormal lipid metabolism. Conclusions Hepatic vagus activity regulates the inflammatory response of Kupffer cells via [alpha]7nAChR in NASH development.