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Rosiglitazone is a synthetic agonist of PPAR\u03b3, whose endogenous agonist is 15\u2010deoxy\u2010\u0394<jats:sup>12,14<\/jats:sup>\u2010PGJ<jats:sub>2<\/jats:sub> (15d\u2010PGJ<jats:sub>2<\/jats:sub>). Reticulon 4B (Nogo\u2010B) is the detectable Nogo protein family member in the liver and secreted into circulation. Here, we determined if rosiglitazone can alleviate intrahepatic cholestasis in mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Wild\u2010type, hepatocyte\u2010specific PPAR\u03b3 or Nogo\u2010B knockout mice received intragastric administration of \u03b1\u2010naphthylisothiocyanate (ANIT) and\/or rosiglitazone, followed by determination of intrahepatic cholestasis and the involved mechanisms. Serum samples from primary biliary cholangitis (PBC) patients and non\u2010PBC controls were analysed for cholestasis\u2010related parameters.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Rosiglitazone prevented wild type, but not hepatocyte\u2010specific PPAR\u03b3 deficient mice from developing ANIT\u2010induced intrahepatic cholestasis by increasing expression of bile homeostatic proteins, reducing hepatic necrosis, and correcting abnormal serum parameters and enterohepatic circulation of bile. Nogo\u2010B knockout provided protection similar to that of rosiglitazone treatment. ANIT\u2010induced intrahepatic cholestasis decreased 15d\u2010PGJ<jats:sub>2<\/jats:sub> but increased Nogo\u2010B in serum, and both were corrected by rosiglitazone. Nogo\u2010B deficiency in the liver increased 15d\u2010PGJ<jats:sub>2<\/jats:sub> production, thereby activating expression of PPAR\u03b3 and bile homeostatic proteins. Rosiglitazone and Nogo\u2010B deficiency also alleviated cholestasis\u2010associated dyslipidemia. In addition, rosiglitazone reduced symptoms of established intrahepatic cholestasis in mice. In serum from PBC patients, the decreased 15d\u2010PGJ<jats:sub>2<\/jats:sub> and increased Nogo\u2010B levels were significantly correlated with classical cholestatic markers.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>Levels of 15d\u2010PGJ<jats:sub>2<\/jats:sub> and Nogo are important biomarkers for intrahepatic cholestasis. Synthetic agonists of PPAR\u03b3 could be used for treatment of intrahepatic cholestasis and cholestasis\u2010associated dyslipidemia.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.14886","type":"journal-article","created":{"date-parts":[[2019,10,28]],"date-time":"2019-10-28T22:19:52Z","timestamp":1572301192000},"page":"1041-1060","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Rosiglitazone alleviates intrahepatic cholestasis induced by \u03b1\u2010naphthylisothiocyanate in mice: The role of circulating 15\u2010deoxy\u2010\u0394<sup>12,14<\/sup>\u2010PGJ<sub>2<\/sub> and Nogo"],"prefix":"10.1111","volume":"177","author":[{"given":"Shuang","family":"Zhang","sequence":"first","affiliation":[{"name":"College of Life Sciences, Key Laboratory of Bioactive Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology Nankai University  Tianjin 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