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LIVER AND BILIARY TRACT

Reduced liver fibrosis in hypoxia-inducible factor-1-deficient mice

¹Department of Pharmacology, Toxicology, and Experimental Therapeutics, University of Kansas Medical Center, Kansas City, Kansas; ²Department of Pharmacy, Pusan National University, Busan, South Korea; and ³Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

Submitted 9 June 2008 ; accepted in final form 5 January 2009

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-1 (HIF-1) 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-1 protein was increased in the livers of mice subjected to BDL by 3 days after surgery. To test the hypothesis that HIF-1 is required for the development of fibrosis, control and HIF-1-deficient mice were subjected to BDL. Levels of type I collagen and -smooth muscle actin mRNA and protein were increased in control mice by 14 days after BDL. These levels were significantly reduced in HIF-1-deficient mice. Next, the levels of several profibrotic mediators were measured to elucidate the mechanism by which HIF-1 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-1-deficient mice at 7 and 14 days after BDL. Results from these studies suggest that HIF-1 is a critical regulator of profibrotic mediator production during the development of liver fibrosis.

cholestasis; bile duct ligation; platelet-derived growth factor; collagen; -smooth muscle actin