Smad3 Deficiency Counteracts Hepatocyte Apoptosis and Portal Fibrogenesis Induced By Bile Duct Ligation
|Misako Sato1,2, Kathleen C Flanders1*, Tsutomu Matsubara3, Yasuteru Muragaki2, Shizuya Saika4and Akira Ooshima1,2|
|1Laboratory of Cancer Biology and Genetics, National Institutes of Health, Bethesda, Maryland, USA|
|2Department of Pathology, Wakayama Medical University, Wakayama, Japan|
|3Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka City University, Japan|
|4Department of Ophthalmology, Wakayama Medical University, Wakayama, Japan|
|Corresponding Author :||Kathleen C Flanders
Laboratory of Cancer Biology and Genetics
National Institutes of Health, NCI/LCBG
Bldg 37/Rm 5046B, 37 Convent Dr
Bethesda, MD 20892, USA
E-mail: [email protected]
|Received November 04, 2013; Accepted January 09, 2014; Published January 17, 2014|
|Citation: Sato M, Flanders KC, Matsubara T, Muragaki Y, Saika S, et al. (2014) Smad3 Deficiency Counteracts Hepatocyte Apoptosis and Portal Fibrogenesis Induced By Bile Duct Ligation. J Liver 3:145. doi: 10.4172/2167-0889.1000145|
|Copyright: © 2014 Sato M, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.|
Objectives: Transforming Growth Factor (TGF)-β is reportedly upregulated and plays a critical role in hepatic fibrogenesis. We aim to study the role of the Smad3, a key transcription factor downstream of TGF-β receptors, signaling pathway in the pathogenesis of cholestatic liver injury induced by Bile Duct Ligation (BDL).
Materials and methods: We used mice lacking Smad3 (Smad3ex8/ex8), and their wild-type littermates to model hepatic fibrosis using BDL. The underlying biology was investigated using histopathological examination and primary cultures of hepatocytes and biliary epithelial cells.
Results: Here we found that mice lacking Smad3 are protected against cholestatic liver injury induced by BDL as evidenced by the absence of hepatocyte apoptosis and portal fibroproliferative responses,including excessive collagen deposition and periductalmyofibroblast proliferation. Smad3-null mice are also shown to reverse the hepatic TGF-β1 upregulation after BDL. In vitro study demonstrates that TGF-β1 expression in primary hepatocytes and intrahepatic biliary epithelial cells is amplified by TGF-β1 itself through a positive feedback loop dependent on Smad3. Culture of primary hepatocytes confirmsthat Smad3 is indispensable for TGF-β1-induced apoptosis.
Conclusions: The data demonstrate that Smad3 plays principal roles in the pathogenesis of BDL-induced cholestatic liver injury and suggest that intervention in this pathway may provide a novel therapeutic approach in the treatment of hepatic fibrosis.