TY - JOUR
T1 - E3 ubiquitin ligase synoviolin is involved in liver fibrogenesis
AU - Hasegawa, Daisuke
AU - Fujii, Ryoji
AU - Yagishita, Naoko
AU - Matsumoto, Nobuyuki
AU - Aratani, Satoko
AU - Izumi, Toshihiko
AU - Azakami, Kazuko
AU - Nakazawa, Minako
AU - Fujita, Hidetoshi
AU - Sato, Tomoo
AU - Araya, Natsumi
AU - Koike, Junki
AU - Tadokoro, Mamoru
AU - Suzuki, Noboru
AU - Nagata, Kazuhiro
AU - Senoo, Haruki
AU - Friedman, Scott L.
AU - Nishioka, Kusuki
AU - Yamano, Yoshihisa
AU - Itoh, Fumio
AU - Nakajima, Toshihiro
N1 - Funding Information:
The authors received funding from Mochida Pharmaceutical Company, Mitsui Life Insurance Company, and Kanto Bureau of Economy, Trade and Industry. However, they do not have any competing interest (employment, consultancy, patents, products in development or marketed products etc). That funding does not alter the authors' adherence to all the PLoS ONE policies, including sharing data and materials.
PY - 2010
Y1 - 2010
N2 - Background and Aim: Chronic hepatic damage leads to liver fibrosis, which is characterized by the accumulation of collagen-rich extracellular matrix. However, the mechanism by which E3 ubiquitin ligase is involved in collagen synthesis in liver fibrosis is incompletely understood. This study aimed to explore the involvement of the E3 ubiquitin ligase synoviolin (Syno) in liver fibrosis. Methods: The expression and localization of synoviolin in the liver were analyzed in CCl4-induced hepatic injury models and human cirrhosis tissues. The degree of liver fibrosis and the number of activated hepatic stellate cells (HSCs) was compared between wild type (wt) and Syno+/- mice in the chronic hepatic injury model. We compared the ratio of apoptosis in activated HSCs between wt and Syno+/- mice. We also analyzed the effect of synoviolin on collagen synthesis in the cell line from HSCs (LX-2) using siRNA-synoviolin and a mutant synoviolin in which E3 ligase activity was abolished. Furthermore, we compared collagen synthesis between wt and Syno-/-mice embryonic fibroblasts (MEF) using quantitative RT-PCR, western blotting, and collagen assay; then, we immunohistochemically analyzed the localization of collagen in Syno-/- MEF cells. Results: In the hepatic injury model as well as in cirrhosis, synoviolin was upregulated in the activated HSCs, while Syno+/- mice developed significantly less liver fibrosis than in wt mice. The number of activated HSCs was decreased in Syno+/- mice, and some of these cells showed apoptosis. Furthermore, collagen expression in LX-2 cells was upregulated by synoviolin overexpression, while synoviolin knockdown led to reduced collagen expression. Moreover, in Syno-/- MEF cells, the amounts of intracellular and secreted mature collagen were significantly decreased, and procollagen was abnormally accumulated in the endoplasmic reticulum. Conclusion: Our findings demonstrate the importance of the E3 ubiquitin ligase synoviolin in liver fibrosis.
AB - Background and Aim: Chronic hepatic damage leads to liver fibrosis, which is characterized by the accumulation of collagen-rich extracellular matrix. However, the mechanism by which E3 ubiquitin ligase is involved in collagen synthesis in liver fibrosis is incompletely understood. This study aimed to explore the involvement of the E3 ubiquitin ligase synoviolin (Syno) in liver fibrosis. Methods: The expression and localization of synoviolin in the liver were analyzed in CCl4-induced hepatic injury models and human cirrhosis tissues. The degree of liver fibrosis and the number of activated hepatic stellate cells (HSCs) was compared between wild type (wt) and Syno+/- mice in the chronic hepatic injury model. We compared the ratio of apoptosis in activated HSCs between wt and Syno+/- mice. We also analyzed the effect of synoviolin on collagen synthesis in the cell line from HSCs (LX-2) using siRNA-synoviolin and a mutant synoviolin in which E3 ligase activity was abolished. Furthermore, we compared collagen synthesis between wt and Syno-/-mice embryonic fibroblasts (MEF) using quantitative RT-PCR, western blotting, and collagen assay; then, we immunohistochemically analyzed the localization of collagen in Syno-/- MEF cells. Results: In the hepatic injury model as well as in cirrhosis, synoviolin was upregulated in the activated HSCs, while Syno+/- mice developed significantly less liver fibrosis than in wt mice. The number of activated HSCs was decreased in Syno+/- mice, and some of these cells showed apoptosis. Furthermore, collagen expression in LX-2 cells was upregulated by synoviolin overexpression, while synoviolin knockdown led to reduced collagen expression. Moreover, in Syno-/- MEF cells, the amounts of intracellular and secreted mature collagen were significantly decreased, and procollagen was abnormally accumulated in the endoplasmic reticulum. Conclusion: Our findings demonstrate the importance of the E3 ubiquitin ligase synoviolin in liver fibrosis.
UR - http://www.scopus.com/inward/record.url?scp=78149455402&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0013590
DO - 10.1371/journal.pone.0013590
M3 - Article
C2 - 21049091
AN - SCOPUS:78149455402
SN - 1932-6203
VL - 5
JO - PLoS ONE
JF - PLoS ONE
IS - 10
M1 - e13590
ER -