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Although the inflammatory interleukin-6 (IL-6)\u2013axis is a crucial factor that drives the hepatic APR by releasing diverse acute-phase proteins (APPs), therapeutic strategies to block the IL-6\u2013STAT3-mediated APR are not well developed. Here, we show that the nuclear receptor retinoic acid-related orphan receptor \u03b1 (ROR\u03b1) limits APR-mediated liver injury by inhibiting the hepatic IL-6\u2013STAT3 signaling pathway. Administration of JC1-40, an ROR\u03b1 activator, diminished diethylnitrosamine-induced acute liver injury and repressed transcriptional expression of APPs such as CXCL1 and LCN2 in mice. IL-6-mediated activation of STAT3 was repressed after ROR\u03b1 activation by either adenoviral infusion of ROR\u03b1 or JC1-40 treatment in primary hepatocytes. Activation of ROR\u03b1 decreased transcriptional expression of IL-6 receptor \u03b1, an upstream activator of STAT3, both <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic>. This may be one mechanism underlying the ROR\u03b1-mediated inhibition of STAT3. Taken together, our results suggest that ROR\u03b1 is a regulator of the hepatic IL-6\u2013STAT3 signaling pathway and may be a new therapeutic target for treating APR-associated inflammatory ALF.<\/jats:p>","DOI":"10.1038\/s41598-019-48171-8","type":"journal-article","created":{"date-parts":[[2019,8,13]],"date-time":"2019-08-13T10:02:28Z","timestamp":1565690548000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["ROR\u03b1 suppresses interleukin-6-mediated hepatic acute phase response"],"prefix":"10.1038","volume":"9","author":[{"given":"Ju-Yeon","family":"Kim","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong-Hyun","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min-Woo","family":"Nam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyeon-Ji","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1578-8211","authenticated-orcid":false,"given":"Mi-Ock","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,8,13]]},"reference":[{"key":"48171_CR1","doi-asserted-by":"publisher","first-page":"1170","DOI":"10.1056\/NEJMc1400974","volume":"370","author":"W Bernal","year":"2014","unstructured":"Bernal, W. & Wendon, J. 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