In DEN-treated mice, vascular endothelial growth factor (VEGF) is

In DEN-treated mice, vascular endothelial growth factor (VEGF) isoforms were increased with increasing time of treatment, becoming strongly positive by northern blot and immunohistochemical staining by 8 weeks of DEN treatment, and were correlated with increase in tissue hypoxia as observed by pimonidazole staining.11 In vitro models have been in concordance with

the previous Selleck PF01367338 findings. Stellate cell activation has been described as an initiating factor in liver fibrosis, and stellate cells cultured under hypoxia had increased collagen mRNA transcripts.11 Exposure of the hepatic stellate cell line LX-2 to hypoxia stimulated HIF1α and VEGF mRNA accumulation by 8 hours, and was associated with evidence of increased signaling through the transforming growth factor-beta (TGF-β)-SMAD dependent pathway. Comparison of a gene array using LX-2 cells in normoxia and hypoxia revealed several targets, including fibroblast growth factor-4, that have been implicated in fibrogenesis or inflammation.79, 80 Another study also reported activation of hepatic stellate cells (HSCs) by hypoxia and demonstrated that this activation was accompanied by secretion of proangiogenic cytokines, such as VEGF and ANG-1, which were

able to stimulate HSC chemotaxis in an autocrine or paracrine fashion. Isolated stellate cells from HIF1α(−/−) mice also demonstrated that genes involved in fibrosis, including angiogenic and collagen-deposition factors, were at least partially dependent on functional HIF1α.81 More recent work has argued for a dominant role for HIF2α in regulating hepatic fibrogenesis in the setting of steatohepatitis. Simultaneous, hepatocyte-specific VHL and HIF1α or HIF2α mouse mutants were generated and assessed for a number of fibrotic

markers. The authors described that when mice with disruption of VHL (e.g., with increased expression of HIF1α and HIF2α) selleck were treated for 2 weeks with an ethanol-containing diet, they developed increased fibrosis and increased expression of the fibrosis marker smooth muscle actin. However, when simultaneous deletion of HIF2α, but not HIF1α, was carried out, this increase was prevented.71 Several studies have illuminated the role of HIFs in the pathogenesis of viral hepatitis, including hepatitis B, hepatitis C, and hepatitis E. In a series of hepatocellular carcinoma (HCC) cases secondary to primary HBV infection, hepatitis B virus X protein (HBx) was found to correlate with HIF1α expression, and transfection of HBx in HepG2 cells was found to increase HIF1α protein accumulation.82 An earlier study similarly reported the stabilization of HIF1α protein in the presence of the HBx protein, and that this stability correlated with promoter activity of HIF1 at the multidrug resistance-1 (MDR-1) protein, an efflux drug transporter thought to be primarily responsible for chemoresistance in HCC.

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