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(American Journal of Pathology. 2003;163:1653-1662.)
© 2003 American Society for Investigative Pathology

Animal Model

Role of Fibroblast Growth Factor Type 1 and 2 in Carbon Tetrachloride-Induced Hepatic Injury and Fibrogenesis

Chundong Yu*§, Fen Wang{dagger}, Chengliu Jin{dagger}, Xinqiang Huang{dagger}, David L. Miller{ddagger}, Claudio Basilico{ddagger} and Wallace L. McKeehan{dagger}

From the Department of Biochemistry and Biophysics,* Texas A&M University, and the Center for Cancer Biology and Nutrition,{dagger} Institute of Biosciences and Technology, Texas A&M University System Health Science Center, Houston, Texas; the Graduate School of Biomedical Sciences,§ The University of Texas–Houston Health Science Center, Houston, Texas; and the Department of Microbiology,{ddagger} New York University School of Medicine, New York, New York

Genomic ablation of hepatocyte-specific fibroblast growth factor receptor (FGFR)4 in mice revealed a role of FGF signaling in cholesterol and bile acid metabolism and hepatolobular restoration in response to injury without effect on liver development or hepatocyte proliferation. Although the potential role of all 23 FGF polypeptides in the liver is still unclear, the most widely studied prototypes, FGF1 and FGF2, are present and have been implicated in liver cell growth and function in vitro. To determine whether FGF1 and FGF2 play a role in response to injury and fibrosis, we examined the impact of both acute and chronic exposure to carbon tetrachloride (CCl4) in the livers of FGF1- and FGF2-deficient mice. After acute CCl4 exposure, FGF1(-/-)FGF2(-/-) mice exhibited an accelerated release of serum alanine aminotransferase similar to FGFR4 deficiency, but no effect on overall hepatolobular restoration or bile acid metabolism. FGF1(-/-)FGF2(-/-) mice exhibited a normal increase in {alpha}-smooth muscle actin and desmin associated with activation and migration of hepatic stellate cells to damage, but a reduced level of hepatic stellate cell-derived matrix collagen {alpha}1(I) synthesis. Liver fibrosis resulting from chronic CCl4 exposure was markedly decreased in the livers of FGF1/FGF2-deficient mice. These results suggest an agonist role for FGF1 and FGF2 in specifically insult-induced liver matrix deposition and hepatic fibrogenesis and a potential target for the prevention of hepatic fibrosis.




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