Na+/H+ exchanger mediates TNF-α-induced hepatocyte apoptosis via the calpain-dependent degradation of Bcl-xL |
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Authors: | Zhan Liu Shuangxi Wang Huixin Zhou Yuming Yang Mingliang Zhang |
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Affiliation: | Department of Gastroenterology, The First Affiliated Hospital of Hunan Normal University (People's Hospital of Hunan Province), Changsha City;;Department of Medicine, The University of Oklahoma, Oklahoma City, Oklahoma, USA;and;Department of Gastroenterology, The Second Affiliated Hospital of Nanhua University, Hengyang City, Hunan, China |
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Abstract: | Background and Aim: It is well known that tumor necrosis factor-α (TNF-α) induces hepatocyte apoptosis and contributes to liver diseases. However, the exact mechanisms are not well understood. Methods: In the present study, we reported that Na+/H+ exchanger (NHE) is involved in TNF-α-induced hepatocyte apoptosis. Results: TNF-α time dependently induced an increase in NHE activity in hepatocytes, but cariporide, an NHE inhibitor, blocked the TNF-α-induced increase of NHE activity in a dose-dependent manner. Increased NHE activity induced by TNF-α was associated with increased intracellular calcium (Ca2+i) concentration and calpain activity. Cariporide reversed these effects induced by TNF-α. In addition, TNF-α downregulated Bcl-xL, an anti-apoptotic protein, but not mRNA levels. The inhibition of either calpain or NHE blocked the TNF-α-induced decrease of the Bcl-xL protein. TNF-α did not change the pro-apoptotic Bax and Bak protein levels. Cariporide, calcium remover 1,2-bis (2-aminophenoxy) ethane-N,N,N0,N0–tetraacetic acid, or calpain inhibitor benzyloxycarbonyl-leucyl-leucinal attenuated TNF-α-induced hepatocyte apoptosis. Conclusion: TNF-α via NHE results in hepatocyte apoptosis through the calcium/calpain/Bcl-xL pathway. |
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Keywords: | apoptosis Bcl-xL calpain hepatocyte Na+/H+ exchanger tumor necrosis factor-α |
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