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Hypoxia‐inducible factor‐1α activation in hepatocytes promotes liver regeneration after acetaminophen overdose
Author(s) -
Copple Bryan Lloyd,
Luyendyk James P
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.257.4
Subject(s) - liver injury , hepatocyte , acetaminophen , liver regeneration , hypoxia (environmental) , hepatoprotection , hypoxia inducible factors , endocrinology , pharmacology , chemistry , medicine , regeneration (biology) , biology , glutathione , biochemistry , microbiology and biotechnology , enzyme , oxygen , gene , organic chemistry , in vitro
Acetaminophen (APAP)‐induced liver injury is a leading cause of drug‐induced liver injury. Global hypoxia‐inducible factor‐1α (HIF‐1α) deficiency transiently reduced APAP‐induced liver injury in mice. The cellular source of HIF‐1α that promotes APAP‐induced liver injury is not known. We tested the hypothesis that activation of HIF‐1α in hepatocytes promotes APAP‐induced liver injury. Hepatocyte‐specific HIF‐1α‐deficient mice (HIF‐1α flox/flox /Albumin‐Cre mice) and control mice (HIF‐1α flox/flox mice) were treated with APAP (300 mg/kg, ip) and both liver injury and regeneration assessed 24 hours later. In contrast to global HIF‐1α deficiency, hepatocyte HIF‐1α deficiency did not reduce liver injury. Rather, liver injury was modestly increased in hepatocytes‐pecific HIF‐1α‐deficient mice treatment. Moreover, hepatic cyclin D1 mRNA levels and the number of PCNA‐positive hepatocytes was substantially reduced in hepatocyte specific‐HIF‐1α‐deficient mice 24 hours after APAP administration, implicating HIF‐1α as a promoter of liver regeneration after APAP overdose. Collectively, the results indicate that activation of HIF‐1α in hepatocytes protects the liver after APAP exposure by promoting liver regeneration.