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

TitleReg2 inactivation increases sensitivity to Fas hepatotoxicity and delays liver regeneration post-hepatectomy in mice.
Publication TypeJournal Article
Year of Publication2006
AuthorsLieu H-T, Simon M-T, Nguyen-Khoa T, Kebede M, Cortes A, Tebar L, Smith AG, Bayne R, Hunt SP, Bréchot C, Christa L
JournalHepatology
Volume44
Issue6
Pagination1452-64
Date Published2006 Dec
ISSN0270-9139
KeywordsAnimals, Antibodies, Monoclonal, Antigens, CD95, Antigens, Neoplasm, DNA, Drug-Induced Liver Injury, Extracellular Signal-Regulated MAP Kinases, Hepatectomy, Humans, Hydrazines, Interleukin-6, Lectins, C-Type, Liver Regeneration, Mice, Mice, Transgenic, Oncogene Protein v-akt, Proteins, Pyrazines, Quinolines, Signal Transduction, Tumor Markers, Biological, Tumor Necrosis Factor-alpha
Abstract

Reg2/RegIIIbeta is the murine 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 microg/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-alpha/IL-6 priming signaling by exerting a negative feed-back 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-alpha/IL6/STAT3 signaling. In contrast, overexpression 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.

DOI10.1002/hep.21434
Alternate JournalHepatology
PubMed ID17133485
Grant ListG0000865 / / Medical Research Council / United Kingdom