Gastroenterology

Gastroenterology

Volume 134, Issue 7, June 2008, Pages 2122-2131
Gastroenterology

Basic—Liver, Pancreas, and Biliary Tract
The Hepatic Vagus Nerve Attenuates Fas-Induced Apoptosis in the Mouse Liver via α7 Nicotinic Acetylcholine Receptor

https://doi.org/10.1053/j.gastro.2008.03.005Get rights and content

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.

Section snippets

Animals

Male C57BL/6 (B6) mice (8 weeks of age; Charles River Japan, Shizuoka, Japan) were kept on a 12-hour light/12-hour dark cycle (room temperature, 23°C–25°C) with food and water freely available. This experiment was reviewed by the Ethics Committee on Animal Experiments of the Graduate School of Medical Sciences, Kyushu University, and was carried out under the control of the Guidelines for Animal Experiments of the Graduate School of Medical Sciences, Kyushu University, and Law (No. 105) and

Validity of Selective Hepatic Vagotomy

All mice were alive after selective denervation of the hepatic vagus nerve, and food intake, weight gain, and behavior in the vagotomized mice were not different from those in the sham-operated mice. There was no significant difference in the norepinephrine level between the sham-operated and vagotomized livers (50.1 ± 8.40 and 64.2 ± 15.6 ng/g tissue, respectively, n = 10 per group). The urine densities in the vagotomized mice were significantly lower than those in the sham-operated mice at 18

Discussion

In this study, we found that hepatic vagus nerve denervation exaggerated Fas-induced fulminant hepatitis. Supplementation with nicotine and PNU-282987, an α7 nicotinic AChR agonist, completely inhibited such an exaggeration, although these supplementations failed to affect in vitro Fas-induced hepatocyte apoptosis. Furthermore, the accelerating effect of the hepatic vagotomy was completely suppressed by the elimination of Kupffer cells. These findings indicate that the hepatic vagus nerve

References (43)

  • Y. Chida et al.

    Electric foot shock stress-induced exacerbation of α-galactosylceramide-triggered apoptosis in mouse liver

    Hepatology

    (2004)
  • Y. Chida et al.

    The hepatic sympathetic nerve plays a critical role in preventing Fas induced liver injury in mice

    Gut

    (2005)
  • Y. Chida et al.

    Does stress exacerbate liver diseases?

    J Gastroenterol Hepatol

    (2006)
  • M. Yoneda et al.

    Central regulation of hepatic function by neuropeptides

    J Gastroenterol

    (2001)
  • A. Adachi et al.

    An hepatic osmoreceptor mechanism in the rat

    Am J Physiol

    (1976)
  • C.T. Simons et al.

    Signaling the brain in systemic inflammation: which vagal branch is involved in fever genesis?

    Am J Physiol

    (1998)
  • K.J. Tracey

    The inflammatory reflex

    Nature

    (2002)
  • L.V. Borovikova et al.

    Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin

    Nature

    (2000)
  • T.R. Bernik et al.

    Pharmacological stimulation of the cholinergic antiinflammatory pathway

    J Exp Med

    (2002)
  • H. Wang et al.

    Nicotinic acetylcholine receptor α7 subunit is an essential regulator of inflammation

    Nature

    (2003)
  • S. Guarini et al.

    Adrenocorticotropin reverses hemorrhagic shock in anesthetized rats through the rapid activation of a vagal anti-inflammatory pathway

    Cardiovasc Res

    (2004)
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      Accumulating evidence has demonstrated that the vagus nerve plays a crucial role in the brain-liver interaction [46]. The vagus nerve is a mixed nerve composed of 20% efferent and 80% afferent fibers [46]. Previous studies also reported that hepatic peroxisome proliferators-activated receptor γ (PPAR-γ) and glucokinase affects SNS activity through the afferent vagal signals originating in the liver [6,47].

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    Supported by Grants-in-aid for General Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology, Japan (No. 16390200, No. 17390210, No. 17659205, and No. 19390192); the Smoking Research Foundation (Japan); the Sumitomo Life Social Welfare Services Foundation (Japan); the Kanae Foundation for the Promotion of Medical Science (Japan); and the British Heart Foundation (United Kingdom).

    Conflicts of interest and financial disclosures: All the authors declare that no potential competing interests exist.

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