Journal
JOURNAL OF GASTROENTEROLOGY
Volume 52, Issue 8, Pages 965-976Publisher
SPRINGER JAPAN KK
DOI: 10.1007/s00535-016-1304-z
Keywords
NASH; NAFLD; Fatty liver disease; alpha 7nAChR; Vagotomy
Categories
Funding
- Japan Society for the Promotion of Science [15K15495]
- Ministry of Education, Culture, Sports, Science and Technology of Japan [26461909]
- Ministry of Health, Labor and Welfare of Japan
- Grants-in-Aid for Scientific Research [15K15495, 26461909] Funding Source: KAKEN
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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. 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. 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. Hepatic vagus activity regulates the inflammatory response of Kupffer cells via alpha 7nAChR in NASH development.
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