Reg2 inactivation increases sensitivity to Fas hepatotoxicity and delays liver regeneration post-hepatectomy in mice

Hanh Tu Lieu, Marie Thérèse Simon, Thao Nguyen-Khoa, Messeret Kebede, Alexandre Cortes, Luis Tebar, Andrew J H Smith, Rosemary Bayne, Stephen P. Hunt, Christian Bréchot, Laurence Christa*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Reg2/RegIIIβ is the marine homologue of the human secreted HIP/PAP C-type lectin. HIP/PAP transgenic mice were protected against acetaminophen-induced acute liver failure and were stimulated to regenerate post-hepatectomy. To assess the role of Reg2, we used Reg2-/- mice in a model of fulminant hepatitis induced by Fas and in the post-hepatectomy regeneration. Within 4 hours of J0-2 treatment (0.5 μg/g), only 50% of the Reg2-/-mice were alive but with an increased sensitivity to Fas-induced oxidative stress and a decreased level of Bcl-xL. In contrast, HIP/PAP transgenic mice were resistant to Fas, with HIP/PAP serving as a sulfhydryl buffer to slow down decreases in glutathione and Bcl-xL. In Reg2-/- mice, liver regeneration was markedly impaired, with 29% mortality and delay of the S-phase and the activation of ERK1/2 and AKT. Activation of STAT3 began on time at 3 hours but persisted strongly up to 72 hours despite significant accumulation of SOCS3. Thus, Reg2 deficiency induced exaggerated IL-6/STAT-3 activation and mito-inhibition. Because the Reg2 gene was activated between 6 and 24 hours after hepatectomy in wild-type mice, Reg2 could mediate the TNF-α/IL-6 priming signaling by exerting a negative feedback on STAT3/IL-6 activation to allow the hepatocytes to progress through the cell cycle. In conclusion, Reg2 deficiency enhanced liver sensitivity to Fas-induced oxidative stress and delayed liver regeneration with persistent TNF-α/IL6/STAT3 signaling. In contrast, over-expression of human HIP/PAP promoted liver resistance to Fas and accelerated liver regeneration with early activation/deactivation of STAT3. Reg2/HIP/PAP is therefore a critical mitogenic and antiapoptotic factor for the liver.

Original languageEnglish
Pages (from-to)1452-1464
Number of pages13
JournalHepatology
Volume44
Issue number6
DOIs
Publication statusPublished - 1 Dec 2006

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