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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Available from: Jeon-Ok Moon, Mar 31, 2014
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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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    ABSTRACT: Macrophages play an integral role in the development of liver fibrosis by releasing mediators, such as platelet-derived growth factor-B (PDGF-B) and transforming growth factor-β1, which stimulate hepatic stellate cell proliferation, chemotaxis, and collagen production. However, the mechanism by which chronic liver injury stimulates macrophages to release these mediators is not completely understood. We tested the hypothesis that chronic liver injury activates hypoxia-inducible factor (HIF) transcription factors in macrophages that regulate the production of mediators that promote fibrosis. To test this hypothesis, Cre/lox technology was used to generate myeloid cell-specific HIF-1α or HIF-1β knockout mice. When these mice were subjected to bile duct ligation (BDL), levels of α-smooth muscle actin and type I collagen in the liver were reduced compared with those of mice with normal levels of HIFs. The deficiency of HIFs in macrophages did not affect liver injury or inflammation after BDL but reduced PDGF-B mRNA and protein, suggesting that HIF activation in macrophages may promote fibrosis by regulating the production of PDGF-B. Consistent with a role for HIFs in liver fibrosis in cholestatic liver disease, nuclear HIF-1α protein was present in macrophages, hepatocytes, and fibroblasts in the livers from patients with primary biliary cirrhosis and primary sclerosing cholangitis. These studies demonstrate that HIFs are important regulators of profibrotic mediator production by macrophages during the development of liver fibrosis and suggest that HIFs may be a novel therapeutic target for the treatment of chronic liver disease in patients.
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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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