期刊
HEPATOLOGY COMMUNICATIONS
卷 2, 期 4, 页码 407-420出版社
JOHN WILEY & SONS LTD
DOI: 10.1002/hep4.1158
关键词
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资金
- Takeda Science Foundation
- Japan Agency for Medical Research and Development (AMED) Acceleration Transformative Research for Medical Innovation [JP17im0210105h]
- AMED [JP17fk0210305h]
Hepatocyte apoptosis has been implicated in the progression of nonalcoholic steatohepatitis. However, it is unclear whether the induction of tumor necrosis factor (TNF)-alpha-mediated hepatocyte apoptosis in the simple fatty liver triggers liver fibrosis. To address this question, high-fat diet-fed mice were repeatedly administered D-galactosamine, which increases the sensitivity of hepatocytes to TNF-alpha-mediated apoptosis. In mice treated with a high-fat diet plus D-galactosamine, hepatocyte apoptosis and liver fibrosis were induced, whereas both apoptosis and fibrosis were inhibited in these mice following gut sterilization with antimicrobials or knockout of TNF-alpha. Furthermore, liver fibrosis was diminished when hepatocyte apoptosis was inhibited by expressing a constitutively active inhibitor of nuclear factor kappa B kinase subunit beta. Thus, hepatocyte apoptosis induced by intestinal dysbiosis or TNF-alpha up-regulation in the steatotic liver caused fibrosis. Organ fibrosis, including liver fibrosis, involves the interaction of cyclic adenosine monophosphate-response element-binding protein-binding protein (CBP) and beta-catenin. Here, hepatocyte-specific CBP-knockout mice showed reduced liver fibrosis accompanied by hepatocyte apoptosis diminution; notably, liver fibrosis was also decreased in mice in which CBP was specifically knocked out in collagen-producing cells because the activation of these cells was now suppressed. Conclusion: TNF-alpha-mediated hepatocyte apoptosis induced fibrosis in the steatotic liver, and inhibition of CBP/beta-catenin signaling attenuated the liver fibrosis due to the reduction of hepatocyte apoptosis and suppression of the activation of collagen-producing cells. Thus, targeting CBP/beta-catenin may represent a new therapeutic strategy for treating fibrosis in nonalcoholic steatohepatitis.
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