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

Abstract

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% O2). The cell viability and intracellular ATP levels were measured. The activation of hypoxia-inducible factor-1α (HIF-1α) 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-1α and expression of pyruvate dehydrogenase kinase-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.)

Matrix metalloproteinase 10 contributes to hepatocarcinogenesis in a novel crosstalk with the stromal derived factor 1/C‐X‐C chemokine receptor 4 axis

“…We found that MMP10 was required for up‐regulation of CXCR4 in the liver during HC and also demonstrated that MMP10 can drive CXCR4 expression in human HCC cells. CXCR4 gene expression can be regulated by a variety of environmental cues, including growth factors such as transforming growth factor beta (TGF‐β), hypoxia, and oxidative stress . Hypoxia is certainly a major driver of CXCR4 expression, as we also observed now in HCC cells, being the CXCR4 gene a direct target of hypoxia‐inducible factor 1 alpha (HIF‐1α) .…”

“…Hypoxia is an important factor that contributes to HCC angiogenesis and the metastatic process . Moreover, as mentioned above, the SDF‐1/CXCR4 axis is activated under hypoxic conditions . These notions led us to evaluate the potential influence of hypoxia and SDF‐1 on MMP10 gene expression in HCC cells.…”

“…The acquired response of the MMP10 gene to SDF‐1 in hypoxia may be owing, in part, to the marked induction of CXCR4 expression that occurs when cells are kept in low oxygen tension (Fig. B) . The mitogen‐activated protein kinase/extracellular signal‐regulated kinase (ERK) 1/2 (MEK‐ERK1/2) pathway is a potent activator of MMP10 gene expression and is also triggered by hypoxia and CXCR4 activation .…”

Nrf2 Activation Protects the Liver From Ischemia/Reperfusion Injury in Mice

“…Whole liver extracts were prepared and subjected to Western blot analysis as previously described, 19 using antibodies specific for NQO1, GCL catalytic subunit (GCLc) (Abcam; Cambridge, UK), and β-actin (Sigma, St Lois, MO).…”

Systematic review with meta-analysis: HIF-1α attenuates liver ischemia–reperfusion injury

“…The 31 included animal studies score ranging from 2 to 6 (see Table 2), and contained 4 studies ranked A [18,19,45,50], 23 ranked B [15][16][17]23,24,27,28,[30][31][32][33][34][35][36][37][38]43,44,[46][47][48][49]51], and 4 ranked C [26,29,39,42]. In subject classification, the study of intervention gets the highest marks, owing to better control of temperature and blinded assessment of outcome.…”