Tumor necrosis factor-α-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)-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 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-α. Furthermore, liver fibrosis was diminished when hepatocyte apoptosis was inhibited by expressing a constitutively active inhibitor of nuclear factor κB kinase subunit β. Thus, hepatocyte apoptosis induced by intestinal dysbiosis or TNF-α 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 β-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-α-mediated hepatocyte apoptosis induced fibrosis in the steatotic liver, and inhibition of CBP/β-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/β-catenin may represent a new therapeutic strategy for treating fibrosis in nonalcoholic steatohepatitis. (Hepatology Communications 2018;2:407-420).

• Authors: Yosuke Osawa, Ekumi Kojika, Yukiko Hayashi, Masamichi Kimura, Koji Nishikawa, Sachiyo Yoshio, Hiroyoshi Doi, Tatsuya Kanto, Kiminori Kimura
• Journal: Hepatology communications (Hepatol Commun) Vol. 2 Issue 4 Pg. 407-420 (04 2018) ISSN: 2471-254X [Electronic] United States
• PMID: 29619419 (Publication Type: Journal Article)