Hypoxia-inducible factor-dependent production of profibrotic mediators by hypoxic hepatocytes

Background/Aims During the development of liver fibrosis, mediators are produced that stimulate cells in the liver to differentiate into myofibroblasts and to produce collagen. Recent studies demonstrated that the transcription factor, hypoxia-inducible factor-1 alpha (HIF-1 alpha), is critical for upregulation of profibrotic mediators, such as platelet-derived growth factor-A (PDGF-A), PDGF-B and plasminogen activator inhibitor-1 (PAI-1) in the liver, during the development of fibrosis. What remains unknown is the cell type-specific regulation of these genes by HIF-1 alpha in liver cell types. Accordingly, the hypothesis was tested that HIF-1 alpha is activated in hypoxic hepatocytes and regulates the production of profibrotic mediators by these cells. Methods In this study, hepatocytes were isolated from the livers of control and HIF-1 alpha- or HIF-1 beta-deficient mice and exposed to hypoxia. Results Exposure of primary mouse hepatocytes to 1% oxygen stimulated nuclear accumulation of HIF-1 alpha and upregulated PAI-1, vascular endothelial cell growth factor and the vasoactive peptides adrenomedullin-1 (ADM-1) and ADM-2. In contrast, the levels of PDGF-A and PDGF-B mRNAs were unaffected in these cells by hypoxia. Exposure of HIF-1 alpha-deficient hepatocytes to 1% oxygen only partially prevented upregulation of these genes, suggesting that other hypoxia-regulated transcription factors, such as HIF-2 alpha, may also regulate these genes. In support of this, HIF-2 alpha was activated in hypoxic hepatocytes, and exposure of HIF-1 beta-deficient hepatocytes to 1% oxygen completely prevented upregulation of PAI-1, vascular endothelial cell growth factor and ADM-1, suggesting that HIF-2 alpha may also contribute to upregulation of these genes in hypoxic hepatocytes. Conclusions Collectively, our results suggest that HIFs may be important regulators of profibrotic and vasoactive mediators by hypoxic hepatocytes.