{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T17:28:29Z","timestamp":1790270909612,"version":"4.1.0"},"reference-count":50,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2018,2,13]],"date-time":"2018-02-13T00:00:00Z","timestamp":1518480000000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Hepatology Communications"],"published-print":{"date-parts":[[2018,4]]},"abstract":"<jats:p>Hepatocyte apoptosis has been implicated in the progression of nonalcoholic steatohepatitis. However, it is unclear whether the induction of tumor necrosis factor (TNF)\u2010\u03b1\u2010mediated hepatocyte apoptosis in the simple fatty liver triggers liver fibrosis. To address this question, high\u2010fat diet\u2010fed mice were repeatedly administered D\u2010galactosamine, which increases the sensitivity of hepatocytes to TNF\u2010\u03b1\u2010mediated apoptosis. In mice treated with a high\u2010fat diet plus D\u2010galactosamine, 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\u2010\u03b1. Furthermore, liver fibrosis was diminished when hepatocyte apoptosis was inhibited by expressing a constitutively active inhibitor of nuclear factor \u03baB kinase subunit \u03b2. Thus, hepatocyte apoptosis induced by intestinal dysbiosis or TNF\u2010\u03b1 up\u2010regulation in the steatotic liver caused fibrosis. Organ fibrosis, including liver fibrosis, involves the interaction of cyclic adenosine monophosphate\u2010response element\u2010binding protein\u2010binding protein (CBP) and \u03b2\u2010catenin. Here, hepatocyte\u2010specific CBP\u2010knockout 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\u2010producing cells because the activation of these cells was now suppressed. <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: TNF\u2010\u03b1\u2010mediated hepatocyte apoptosis induced fibrosis in the steatotic liver, and inhibition of CBP\/\u03b2\u2010catenin signaling attenuated the liver fibrosis due to the reduction of hepatocyte apoptosis and suppression of the activation of collagen\u2010producing cells. Thus, targeting CBP\/\u03b2\u2010catenin may represent a new therapeutic strategy for treating fibrosis in nonalcoholic steatohepatitis. 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