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

¹ Department of Psychosomatic Medicine, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan
² Department of Integrative Physiology, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan

Correspondence to:
Correspondence to:
Dr Y Chida
Department of Psychosomatic Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; chidayo{at}cephal.med.kyushu-u.ac.jp

Background: Although previous studies have shown that the hepatic sympathetic nerve controls various physiological functions in the liver, the role of this nerve in liver injury has yet to be clarified.

Aims: The purpose of this study was to elucidate the role of this nerve, based on our newly developed technique for selectively removing the activities of the hepatic sympathetic nerve.

Subjects and methods: Male C57BL/6 mice were operated on for hepatic sympathetic denervation. Thereafter, mice were intravenously administered 0.25 or 0.35 µg/g weight of the Fas agonist antibody, Jo-2, after which mortality by fulminant hepatitis was evaluated. Apoptosis in the liver was also examined by both terminal deoxynucleotidyl transferase mediated dUTP nick end labelling and caspase-3 assay.

Results: Mortality in sympathectomised mice was significantly higher than that in sham operated mice following administration of Jo-2. This result was also supported by apoptosis data in which sympathectomised livers exhibited a significant elevation in the number of apoptotic hepatocytes and caspase-3 activity after Jo-2 treatment compared with sham operated livers. Moreover, pretreatment with norepinephrine dose dependently inhibited the hepatic sympathectomy induced increase in mortality after Jo-2 injection. Antiapoptotic protein levels of FLICE inhibitory protein, Bcl-xL, and Bcl-2 in the liver were significantly lower in sympathectomised mice at one and two hours following Jo-2 treatment than in sham operated animals. In addition, interleukin 6 supplementation dose dependently suppressed the hepatic sympathectomy induced increase in mortality after Jo-2 treatment.

Conclusions: These results suggest that norepinephrine released from the hepatic sympathetic nerve plays a critical role in protecting the liver from Fas mediated fulminant hepatitis, possibly via mechanisms including antiapoptotic proteins and interleukin 6.

Abbreviations: 6-OHDA, 6-hydroxydopamine; NE, norepinephrine; IL-6, interleukin 6; PBS, phosphate buffered saline; TH, tyrosine hydroxylase; H&E, haematoxylin-eosin; TUNEL, terminal deoxynucleotidyl transferase mediated dUTP nick end labelling; FLIP, FLICE inhibitory protein

Keywords: apoptosis; fas; hepatitis; norepinephrine; sympathetic nervous system