{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T22:15:33Z","timestamp":1791670533430,"version":"4.3.4"},"reference-count":36,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","license":[{"start":{"date-parts":[[2019,8,20]],"date-time":"2019-08-20T00:00:00Z","timestamp":1566259200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2019,8,20]],"date-time":"2019-08-20T00:00:00Z","timestamp":1566259200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2020,1]]},"abstract":"<jats:p>Activation of apoptosis signal\u2010regulating kinase 1 (ASK1) is a key driving force of the progression of nonalcoholic steatohepatitis (NASH) and represents an attractive therapeutic target for NASH treatment. However, the molecular and cellular mechanisms underlying ASK1 activation in the pathogenesis of NASH remain incompletely understood. In this study, our data unequivocally indicated that hyperactivated ASK1 in hepatocytes is a potent inducer of hepatic stellate cell (HSC) activation by promoting the production of hepatocyte\u2010derived factors. Our previous serial studies have shown that the ubiquitination system plays a key role in regulating ASK1 activity during NASH progression. Here, we further demonstrated that tumor necrosis factor receptor\u2013associated factor 6 (TRAF6) promotes lysine 6 (Lys6)\u2010linked polyubiquitination and subsequent activation of ASK1 to trigger the release of robust proinflammatory and profibrotic factors in hepatocytes, which, in turn, drive HSC activation and hepatic fibrosis. Consistent with the <jats:italic toggle=\"yes\">in vitro<\/jats:italic> findings, diet\u2010induced liver inflammation and fibrosis were substantially attenuated in <jats:italic toggle=\"yes\">Traf6<\/jats:italic>\n                           <jats:sup>+\/\u2013<\/jats:sup> mice, whereas hepatic TRAF6 overexpression exacerbated these abnormalities. Mechanistically, Lys6\u2010linked ubiquitination of ASK1 by TRAF6 facilitates the dissociation of thioredoxin from ASK1 and N\u2010terminal dimerization of ASK1, resulting in the boosted activation of ASK1\u2010c\u2010Jun N\u2010terminal kinase 1\/2 (JNK1\/2)\u2010mitogen\u2010activated protein kinase 14(p38) signaling cascade in hepatocytes. <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic> These results suggest that Lys6\u2010linked polyubiquitination of ASK1 by TRAF6 represents a mechanism underlying ASK1 activation in hepatocytes and a key driving force of proinflammatory and profibrogenic responses in NASH. Thus, inhibiting Lys6\u2010linked polyubiquitination of ASK1 may serve as a potential therapeutic target for NASH treatment.<\/jats:p>","DOI":"10.1002\/hep.30822","type":"journal-article","created":{"date-parts":[[2019,6,21]],"date-time":"2019-06-21T02:28:55Z","timestamp":1561084135000},"page":"93-111","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":73,"title":["Hepatocyte TNF Receptor\u2013Associated Factor 6 Aggravates Hepatic Inflammation and Fibrosis by Promoting Lysine 6\u2013Linked Polyubiquitination of Apoptosis Signal\u2010Regulating Kinase 1"],"prefix":"10.1097","volume":"71","author":[{"given":"Yutao","family":"Wang","sequence":"first","affiliation":[{"name":"College of Life Sciences, Department of Cardiology,Renmin Hospital of Wuhan University, Wuhan University,Wuhan,China"},{"name":"Institute of Model Animal of Wuhan 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