Article

Reduced Liver Fibrosis in Hypoxia-inducible Factor1α-Deficient Mice

Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, 4063 KLSIC, 3901 Rainbow Blvd., Kansas City, KS 66160, USA.
AJP Gastrointestinal and Liver Physiology (Impact Factor: 3.74). 02/2009; 296(3):G582-92. DOI: 10.1152/ajpgi.90368.2008
Source: PubMed

ABSTRACT Liver fibrosis is characterized by excessive deposition of extracellular matrix in the liver during chronic injury. During early stages of this disease, cells begin to synthesize and secrete profibrotic proteins that stimulate matrix production and inhibit matrix degradation. Although it is clear that these proteins are important for development of fibrosis, what remains unknown is the mechanism by which chronic liver injury stimulates their production. In the present study, the hypothesis was tested that hypoxia-inducible factor-1alpha (HIF-1alpha) is activated in the liver during chronic injury and regulates expression of profibrotic proteins. To investigate this hypothesis, mice were subjected to bile duct ligation (BDL), an animal model of liver fibrosis. HIF-1alpha protein was increased in the livers of mice subjected to BDL by 3 days after surgery. To test the hypothesis that HIF-1alpha is required for the development of fibrosis, control and HIF-1alpha-deficient mice were subjected to BDL. Levels of type I collagen and alpha-smooth muscle actin mRNA and protein were increased in control mice by 14 days after BDL. These levels were significantly reduced in HIF-1alpha-deficient mice. Next, the levels of several profibrotic mediators were measured to elucidate the mechanism by which HIF-1alpha promotes liver fibrosis. Platelet-derived growth factor (PDGF)-A, PDGF-B, and plasminogen activator inhibitor-1 mRNA levels were increased to a greater extent in control mice subjected to BDL compared with HIF-1alpha-deficient mice at 7 and 14 days after BDL. Results from these studies suggest that HIF-1alpha is a critical regulator of profibrotic mediator production during the development of liver fibrosis.

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    • "HIF-1α expression can activate hepatic stellate cells (HSCs) and fibroblasts to differentiate into myofibroblasts that proliferate and migrate to injured areas where they secrete ECM [64] [65] [66] [67]. In vivo studies using bile duct ligated mice; an animal model of liver fibrosis show increased Hif-1α expression 3 days after surgery, whereas Hif-1α deficient ligated mice show a significant reduction in fibrogenic mediators [66]. "
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    • "in the liver was detected using immunohistochemistry and quantified morphometrically by analyzing the area of immunohistochemical staining of type I collagen as described previously by us (Kim et al., 2006; Moon et al., 2009). An increase in the area of type I collagen staining in the liver is an indicator of fibrosis. "
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    • "Additionally, chronic hypoxia and augmented HIF-1 accumulation in fibroblasts of noncutaneous organs is considered to be an important mechanism in the pathogenesis of fibrosis including liver cirrhosis and kidney fibrosis. Further, selective and tissue specific deletion of HIF-1a in liver using a Cre–lox system has been shown to reduce liver fibrosis through reduced myofibroblast transformation, reduced expression of PDGF and PAI-1 and reduced production of collagenous matrix following bile duct ligation (Moon et al., 2009). Similar processes occur in other organs. "
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