Background/Aims
Several studies have shown that regions of hypoxia develop in the liver during chronic injury. Furthermore, it has been demonstrated that hypoxia stimulates the release of mediators from hepatic stellate cells (HSCs) that may affect the progression of fibrosis. The mechanism by which hypoxia modulates gene expression in HSCs is not known. Recent studies demonstrated that the hypoxia-activated transcription factor, hypoxia-inducible factor-1α (HIF-1α), is critical for the development of fibrosis. Accordingly, the hypothesis was tested that HIF-1α is activated in HSCs and regulates expression of genes important for HSC activation and liver fibrosis.
Methods
HSCs were isolated from mice and exposed to hypoxia. HIF-1α and HIF-2α activation were measured, and gene expression analyzed by gene array analysis. To identify genes regulated by HIF-1α, HSCs were isolated from Control and HIF-1α-Deficient mice.
Results
Exposure of primary mouse HSCs to 0.5% oxygen activated HIF-1α and HIF-2α. mRNA levels of numerous genes were increased in HSCs exposed to 0.5% oxygen, many of which are important for HSC function, angiogenesis, and collagen synthesis. Of the mRNAs increased, Ccr1, Ccr5, macrophage migration inhibitory factor, interleukin-13 receptor α1, prolyl-4-hydroxylase α2 (PHD α2) were completely HIF-1α-dependent. Upregulation of VEGF and placental growth factor were partially HIF-1α-dependent and upregulation of angiopoietin-like 4 and PHD α1 were HIF-1α-independent.
Conclusions
Results from these studies demonstrate that hypoxia, through activation of HIF-1α, regulates expression of genes that may alter the sensitivity of HSCs to certain activators and chemotaxins, and regulates expression of genes important for angiogenesis and collagen synthesis.