The Hepatic Vagus Nerve Attenuates Fas-Induced Apoptosis in the Mouse Liver via α7 Nicotinic Acetylcholine Receptor

Tetsuya Hiramoto, Yoichi Chida, Junko Sonoda, Kazufumi Yoshihara, Nobuyuki Sudo, Chiharu Kubo

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57 Citations (Scopus)


Background & Aims: Although accumulating evidence has recently shown that the efferent vagus nerve attenuates systemic inflammation, it remains unclear whether or not the vagus nerve can affect Fas-induced liver apoptosis. We investigated the effect of the vagus nerve by using a selective hepatic vagotomy. Methods: We assessed the mortality and apoptosis in Fas-induced fulminant hepatitis in sham-operated and vagotomized male C57BL/6 mice. To determine how the nerve influences hepatocyte apoptosis, hepatitis was preceded by pretreatment with nicotine; PNU-282987, an α7 nicotinic acetylcholine receptor (AChR) agonist; liposome-encapsulated dichloromethylene diphosphonate (lipo-Cl2MDP), a macrophage eliminator; and Mn (III) tetrakis (4-benzoic acid) porphyrin chloride (MnTBAP), an oxidative inhibitor. Results: Mortality in the vagotomized mice was significantly higher than that in the sham-operated mice following intravenous administration with the anti-Fas antibody Jo-2. This result was also supported by the data from both terminal deoxynucleotidyl-transferase mediated dUTP nick-end labeling and caspase-3 assay, in which vagotomized livers showed a significant elevation in the number of apoptotic hepatocytes and increased caspase-3 activity following Jo-2 treatment compared with the sham-operated livers. Supplementation with nicotine and PNU-282987 dose dependently inhibited this detrimental effect of the vagotomy. Moreover, the vagotomy-triggered exacerbation of Fas-induced hepatitis was completely blocked by lipo-Cl2MDP. Similarly, pretreatment with MnTBAP also completely suppressed the vagotomy-triggered exacerbation. Conclusions: The hepatic vagus nerve appears to play an important role in attenuating Fas-induced hepatocyte apoptosis through α7 nicotinic AChR, perhaps by causing the Kupffer cells to reduce their generation of an excessive amount of reactive oxygen species.

Original languageEnglish
Pages (from-to)2122-2131
Number of pages10
Issue number7
Publication statusPublished - Jun 2008

All Science Journal Classification (ASJC) codes

  • Hepatology
  • Gastroenterology


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