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J. Biol. Chem., Vol. 282, Issue 30, 22089-22101, July 27, 2007

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Transforming Growth Factor-1 Induces an Epithelial-to-Mesenchymal Transition State in Mouse Hepatocytes in Vitro^*

Aki Kaimori, James Potter, Jun-ya Kaimori, Connie Wang¹, Esteban Mezey, and Ayman Koteish²

From the Division of Gastroenterology and Hepatology and Division of Nephrology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

Liver fibrosis is a progressive pathologic process that involves deposition of excess extracellular matrix leading to distorted architecture and culminating in cirrhosis. The role of transforming growth factor- (TGF-) as a key molecule in the development and progression of hepatic fibrosis via the activation of hepatic stellate cells, among other fibroblast populations, is without controversy. We hereby show that TGF-1 induces an epithelial-to-mesenchymal transition (EMT) state in mature hepatocytes in vitro. EMT state was marked by significant upregulation of ₁(I) collagen mRNA expression and type I collagen deposition. Similar changes were found in a "normal" mouse hepatocyte cell line (AML12), thus confirming that hepatocytes are capable of EMT changes and type I collagen synthesis. We also show that in hepatocytes in the EMT state, TGF-1 induces the snail-1 transcription factor and activates the Smad2/3 pathway. Evidence for a central role of the TGF-1/Smad pathway is further supported by the inhibition of EMT by Smad4 silencing using small interference RNA technology. In conclusion, TGF-1, a known pro-apoptotic cytokine in mature hepatocytes, is capable of mediating phenotypic changes and plasticity in the form of EMT, resulting in collagen deposition. Our findings support a potentially crucial role for EMT in the development and progression of hepatic fibrogenesis.

Received for publication, February 2, 2007 , and in revised form, May 16, 2007.

^* This work was supported by National Institutes of Health Grant P50DK57325 and United States Public Health Service Grant AA000626. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Present address: Division of Nephrology and Hypertension, University of Kansas Medical Center, 3901 Rainbow Blvd., Sudler 4015, Mail Stop 3002, Kansas City, KS 66160.

¹ To whom correspondence should be addressed: The Johns Hopkins University School of Medicine, Division of Gastroenterology and Hepatology, 720 Rutland Ave., Ross Research Bldg. 933C, Baltimore, MD 21205. Tel.: 410-614-0144; Fax: 410-955-9677; E-mail: akoteish{at}jhmi.edu.

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