{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T06:03:14Z","timestamp":1790316194592,"version":"4.1.0"},"reference-count":27,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":457,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2014,6]]},"abstract":"<jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      Hepatic stellate cell (HSC) transdifferentiation from a quiescent, adipocyte-like cell to a highly secretory and contractile myofibroblast-like phenotype contributes to negative pathological consequences, including fibrosis\/cirrhosis with portal hypertension (PH). Antiadipogenic mechanisms have been shown to underlie activation of HSCs. We examined the role of heme-sensing nuclear receptor Rev-erb\u03b1, a transcriptional repressor involved in metabolic and circadian regulation known to promote adipogenesis in preadipocytes, in HSC transdifferentiation. We discovered that Rev-erb\u03b1 protein was up-regulated in activated HSCs and injured livers; however, transcriptional repressor activity was not affected by fibrogenic treatments. Surprisingly, increased protein expression was accompanied with increased cytoplasmic accumulation of Rev-erb\u03b1, which demonstrated distributions similar to myosin, the major cellular motor protein. Cells overexpressing a cytoplasm-localized Rev-erb\u03b1 exhibited enhanced contractility. Ectopically expressed Rev-erb\u03b1 responded to both adipogenic ligand and fibrogenic transforming growth factor beta treatment. Rev-erb ligand SR6452 down-regulated cytoplasmic expression of Rev-erb\u03b1, decreased expression of fibrogenic markers and the activated phenotype in HSCs, and ameliorated fibrosis and PH in rodent models.\n                      <jats:italic toggle=\"yes\">Conclusions:<\/jats:italic>\n                      Up-regulation of Rev-erb\u03b1 is an intrinsic fibrogenic response characterized by cytoplasmic accumulation of the protein in activated HSCs. Cytoplasmic expression of Rev-erb\u03b1 promotes a contractile phenotype. Rev-erb\u03b1 acts as a bifunctional regulator promoting either anti- or profibrogenic response, depending on milieu. Rev-erb ligand SR6452 functions by a previously undescribed mechanism, targeting both nuclear activity and cytoplasmic expression of Rev-erb\u03b1. Our studies identify Rev-erb\u03b1 as a novel regulator of HSC transdifferentiation and offers exciting new insights on the therapeutic potential of Rev-erb ligands. (Hepatology 2014;59:2383\u20132396)\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/hep.27049","type":"journal-article","created":{"date-parts":[[2014,2,4]],"date-time":"2014-02-04T17:33:39Z","timestamp":1391535219000},"page":"2383-2396","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":52,"title":["Novel role of nuclear receptor rev-erb\u03b1 in hepatic stellate cell activation: Potential therapeutic target for liver injury"],"prefix":"10.1097","volume":"59","author":[{"given":"Ting","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley L.","family":"Eheim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabine","family":"Klein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank 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