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Tumor necrosis factor-?-mediated hepatocyte apoptosis stimulates fibrosis in the steatotic liver in mice.


ABSTRACT: Hepatocyte apoptosis has been implicated in the progression of nonalcoholic steatohepatitis. However, it is unclear whether the induction of tumor necrosis factor (TNF)-?-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-?-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-?. Furthermore, liver fibrosis was diminished when hepatocyte apoptosis was inhibited by expressing a constitutively active inhibitor of nuclear factor ?B kinase subunit ?. Thus, hepatocyte apoptosis induced by intestinal dysbiosis or TNF-? 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 ?-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-?-mediated hepatocyte apoptosis induced fibrosis in the steatotic liver, and inhibition of CBP/?-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/?-catenin may represent a new therapeutic strategy for treating fibrosis in nonalcoholic steatohepatitis. (Hepatology Communications 2018;2:407-420).

SUBMITTER: Osawa Y 

PROVIDER: S-EPMC5880193 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Tumor necrosis factor-α-mediated hepatocyte apoptosis stimulates fibrosis in the steatotic liver in mice.

Osawa Yosuke Y   Kojika Ekumi E   Hayashi Yukiko Y   Kimura Masamichi M   Nishikawa Koji K   Yoshio Sachiyo S   Doi Hiroyoshi H   Kanto Tatsuya T   Kimura Kiminori K  

Hepatology communications 20180213 4


Hepatocyte apoptosis has been implicated in the progression of nonalcoholic steatohepatitis. However, it is unclear whether the induction of tumor necrosis factor (TNF)-α-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-α-mediated apoptosis. In mice treated with a high-fat diet plus D-galactosamine, hepatocyte apoptos  ...[more]

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