The hepatic vagus nerve attenuates Fas-induced apoptosis in the mouse liver via alpha7 nicotinic acetylcholine receptor

Gastroenterology. 2008 Jun;134(7):2122-31. doi: 10.1053/j.gastro.2008.03.005. Epub 2008 Mar 8.


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 alpha7 nicotinic acetylcholine receptor (AChR) agonist; liposome-encapsulated dichloromethylene diphosphonate (lipo-Cl(2)MDP), 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-Cl(2)MDP. 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 alpha7 nicotinic AChR, perhaps by causing the Kupffer cells to reduce their generation of an excessive amount of reactive oxygen species.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Murine-Derived
  • Antioxidants / pharmacology
  • Apoptosis* / drug effects
  • Benzamides / pharmacology
  • Bridged Bicyclo Compounds / pharmacology
  • Caspase 3 / metabolism
  • Diphosphonates / pharmacology
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Hepatitis / immunology
  • Hepatitis / metabolism*
  • Hepatitis / pathology
  • Hepatitis / prevention & control
  • Kupffer Cells / metabolism
  • Liver / drug effects
  • Liver / enzymology
  • Liver / innervation*
  • Liver / pathology
  • Male
  • Metalloporphyrins / pharmacology
  • Methane / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Nicotine / pharmacology
  • Nicotinic Agonists / pharmacology
  • Reactive Oxygen Species / metabolism
  • Receptors, Nicotinic / drug effects
  • Receptors, Nicotinic / metabolism*
  • Reproducibility of Results
  • Signal Transduction* / drug effects
  • Time Factors
  • Vagotomy
  • Vagus Nerve / metabolism*
  • Vagus Nerve / surgery
  • alpha7 Nicotinic Acetylcholine Receptor
  • fas Receptor / immunology
  • fas Receptor / metabolism*


  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Murine-Derived
  • Antioxidants
  • Benzamides
  • Bridged Bicyclo Compounds
  • Chrna7 protein, mouse
  • Diphosphonates
  • LE-Cl2MDP
  • Metalloporphyrins
  • Nicotinic Agonists
  • PNU-282987
  • Reactive Oxygen Species
  • Receptors, Nicotinic
  • alpha7 Nicotinic Acetylcholine Receptor
  • anti-Fas monoclonal antibody
  • fas Receptor
  • manganese(III)-tetrakis(4-benzoic acid)porphyrin
  • Nicotine
  • Casp3 protein, mouse
  • Caspase 3
  • Methane