Liver epithelial cells proliferate under hypoxia and protect the liver from ischemic injury via expression of HIF-1 alpha target genes

Background. The remnant liver after extended liver resection is susceptible to ischemic injury, resulting in the failure of liver regeneration and liver dysfunction. The present study is aimed to investigate the protective role of the liver epithelial cells (LEC), a liver progenitor cell, on hepatocytes with ischemia in vitro and in vivo. Methods. LECs were isolated from rats and cultured under hypoxic conditions (2% O-2). The cell viability and intracellular ATP levels were measured. The activation of hypoxia-inducible factor-la (HIF-1 alpha) was assessed by immunofluorescence. The expression of pyruvate dehydrogenase kinase-1 (PDK-1), stromal cell-derived factor-1 (SDF-1), and chemokine receptor 4 (CXCR4) were measured. Hepatocytes were treated with SDF-1 or LEC-conditioned medium under hypoxia, and cell viability was assessed. Finally, hemorrhagic shock was induced in rats with in vivo induction of endogenous LECs, and liver damage was assessed. Results. In LECs, but not in hepatocytes, cellular viability and intracellular ATP levels were maintained, and nuclear translocation of HIF-1 alpha and expression of pyruvate dehydrogenase kinase-1 1 mRNA were increased under hypoxic culture conditions. LECs express SDF-1, and CXCR4 expression was increased in hepatocytes under hypoxia. The survival of hepatocytes under hypoxic condition was significantly increased after treatment with SDF-1 or LEC-conditioned medium. The protective effect of conditioned medium was impaired by CXCR4 antagonists. In vivo induction of endogenous LECs suppressed elevation of serum AST and ALT levels after hemorrhage shock and ischemia-reperfusion. Conclusion. LECs are resistant to hypoxia and have a protective role for hepatocytes against hypoxia. Our results suggest that induction of endogenous LECs protected the liver from lethal insults by paracrine signaling of SDF-1 and differentiation into parenchymal cells. (Surgery 2012;152:869-78.)