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Hypoxia‐inducible factor‐1α activation in hepatocytes promotes liver regeneration after acetaminophen overdose

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‐1αflox/flox/Albumin‐Cre mice) and control mice (HIF‐1αflox/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.