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

Abstract

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-1α (HIF-1α), 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-1α in liver cell types. Accordingly, the hypothesis was tested that HIF-1α is activated in hypoxic hepatocytes and regulates production of profibrotic mediators by these cells. Methods In this study, hepatocytes were isolated from the livers of control and HIF-1α or HIF-1β-Deficient mice and exposed to hypoxia. Results Exposure of primary mouse hepatocytes to 1% oxygen stimulated nuclear accumulation of HIF-1α and upregulated PAI-1, vascular endothelial cell growth factor, and the vasoactive peptides adrenomedullin-1 (ADM-1) and ADM-2. In contrast, levels of PDGF-A and PDGF-B mRNAs were unaffected in these cells by hypoxia. Exposure of HIF-1α-Deficient hepatocytes to 1% oxygen only partially prevented upregulation of these genes, suggesting that other hypoxia-regulated transcription factors, such as HIF-2α, may also regulate these genes. In support of this, HIF-2α was activated in hypoxic hepatocytes, and exposure of HIF-1β-Deficient hepatocytes to 1% oxygen completely prevented upregulation PAI-1, VEGF, and ADM-1, suggesting that HIF-2α 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.

Intermedin is overexpressed in hepatocellular carcinoma and regulates cell proliferation and survival

“…(14) Thus, we hypothesized that IMD might be involved in HCC development because neovascularization is a prerequisite for tumor progression. Increased tumor growth leads to hypoxia, which induces the expression of HIF.…”

“…(12) The signaling of IMD is mediated by the interaction of CRLR in association with receptor activity modifying protein 3 (RAMP3). (13) IMD is expressed by endothelial cells, smooth muscle cells and cardiomyocytes at a basal level with enhanced expression in response to hypoxic stress (14) or high blood pressure. (15) In addition, IMD can be induced by hypoxia-inducible factors (HIF) 1a and 1b in hypoxic hepatocytes.…”

“…(15) In addition, IMD can be induced by hypoxia-inducible factors (HIF) 1a and 1b in hypoxic hepatocytes. (14) The calcitonin peptide family, of which IMD is a member, has a common secondary structure with an N-terminal ring structure and an amidated carboxyl terminus. Truncation of the N-terminal ring structure produces antagonist peptides in all family members.…”

“…(13) IMD is expressed by endothelial cells, smooth muscle cells and cardiomyocytes at a basal level with enhanced expression in response to hypoxic stress (14) or high blood pressure.…”

Differential Roles of Angiogenesis in the Induction of Fibrogenesis and the Resolution of Fibrosis in Liver

“…20) VEGF is also upregulated in hypoxic hepatocytes, and inhibition of HIF-1α signaling completely prevents up-regulation of VEGF in such cells. 21) Although hepatocytes are the main cells producing VEGF in the liver, several studies have demonstrated that hypoxia also stimulates VEGF expression in HSCs, 16,22) and others have observed an important autocrine VEGF signaling loop within ECs themselves. 23) HSCs induce fibrosis via collagen and proinflammatory cytokine production but are increasingly recognized for their roles in angiogenesis and vascular remodeling.…”