title: Hepatic vagus nerve regulates Kupffer cell activation via α7 nicotinic acetylcholine receptor in nonalcoholic steatohepatitis.
abstract: 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 α7 nicotinic acetylcholine receptor (α7nAChR) 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. α7nAChR knockout (α7KO) chimeric mice were generated by transplanting α7KO bone marrow cells into irradiated and Kupffer cell-deleted WT recipients. Kupffer cells were isolated from WT mice and treated with α7nAChR 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 (TNFα), interleukin (IL)-12, and monocyte chemoattractant protein 1 (MCP-1), was accelerated in HV mice, accompanied by the downregulation of PPARα pathway genes. Kupffer cells were highly activated via the phosphorylation and nuclear translocation of nuclear factor-kappa B (NF-κB) in MCD diet-fed HV mice. The α7nAchR agonist suppressed the inflammatory response of primary Kupffer cells induced by lipopolysaccharide and palmitic acid by attenuating the NF-κB cascade. α7KO chimeric mice fed an MCD diet for 1 week developed advanced NASH with highly activated Kupffer cells. The hepatic expression of TNFα, IL-12, and MCP-1 was upregulated in α7KO chimeric mice, accompanied by abnormal lipid metabolism.
  
  
  CONCLUSIONS
  Hepatic vagus activity regulates the inflammatory response of Kupffer cells via α7nAChR in NASH development.
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Nishio
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, Japan. ktaura@kuhp.kyoto-u.ac.jp.
authors.forename: Kojiro
authors.initials: K
authors.lastname: Taura
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, Japan.|Department of Target Therapy Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Iwaisako
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, Japan.
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Koyama
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, Japan.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Tanabe
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, Japan.
authors.forename: Gen
authors.initials: G
authors.lastname: Yamamoto
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, Japan.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Okuda
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, Japan.
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Ikeno
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Yoshino
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Kasai
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Okuno
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Seo
authors.affiliation: Department of Diagnostic Pathology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Takaki
authors.initials: T
authors.lastname: Sakurai
authors.affiliation: Innovation Center for Immunoregulation and Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Asagiri
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, Japan.|Department of Surgery, Hyogo College of Medicine, Hyogo, Japan.
authors.forename: Etsuro
authors.initials: E
authors.lastname: Hatano
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Uemoto
mesh_terms: D000818:Animals; D018932:Chemokine CCL2 / Q000235:genetics; D002678:Chimera; D002794:Choline / Q000008:administration & dosage; D002796:Choline Deficiency / Q000378:metabolism; D015536:Down-Regulation; D053765:Interleukin-12 Subunit p35 / Q000235:genetics; D007728:Kupffer Cells / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000294:innervation* / Q000378:metabolism*; D008297:Male; D008715:Methionine / Q000008:administration & dosage / Q000172:deficiency; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism*; D047493:PPAR alpha / Q000235:genetics; D019308:Palmitic Acid / Q000494:pharmacology; D010766:Phosphorylation; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D015854:Up-Regulation; D014628:Vagotomy; D014630:Vagus Nerve / Q000378:metabolism*; D055536:Vagus Nerve Stimulation; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; C508859:Il12a protein, mouse; D053765:Interleukin-12 Subunit p35; D008070:Lipopolysaccharides; D016328:NF-kappa B; D047493:PPAR alpha; D014409:Tumor Necrosis Factor-alpha; D064569:alpha7 Nicotinic Acetylcholine Receptor; D019308:Palmitic Acid; D008715:Methionine; D002794:Choline
keywords: Fatty liver disease; NAFLD; NASH; Vagotomy; α7nAChR