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Recently, we have shown that bilirubin binds directly to the fat-burning nuclear peroxisome proliferator-activated receptor-\u03b1 (PPAR\u03b1). Additionally, we have shown that serine 73 phosphorylation [Ser(P)<jats:sup>73<\/jats:sup>] of PPAR\u03b1 decreases activity by reducing its protein levels and transcriptional activity. The aim of this study was to determine whether humanized mice with the Gilbert\u2019s polymorphism (HuUGT*28) have increased PPAR\u03b1 activation and reduced hepatic fat accumulation. To determine whether humanized mice with Gilbert\u2019s mutation (HuUGT*28) have reduced hepatic lipids, we placed them and C57BL\/6J control mice on a high-fat (60%) diet for 36 wk. Body weights, fat and lean mass, and fasting blood glucose and insulin levels were measured every 6 wk throughout the investigation. At the end of the study, hepatic lipid content was measured and PPAR\u03b1 regulated genes as well as immunostaining of Ser(P)<jats:sup>73<\/jats:sup>PPAR\u03b1 from liver sections. The HuUGT*28 mice had increased serum bilirubin, lean body mass, decreased fat mass, and hepatic lipid content as well as lower serum glucose and insulin levels. Also, the HuUGT*28 mice had reduced Ser(P)<jats:sup>73<\/jats:sup>PPAR\u03b1 immunostaining in livers and increased PPAR\u03b1 transcriptional activity compared with controls. A chronic but mild endogenous increase in unconjugated hyperbiliubinemia protects against hepatic steatosis through a reduction in Ser(P)<jats:sup>73<\/jats:sup>PPAR\u03b1, causing an increase in PPAR\u03b1 transcriptional activity.<\/jats:p>","DOI":"10.1152\/ajpendo.00396.2016","type":"journal-article","created":{"date-parts":[[2017,1,18]],"date-time":"2017-01-18T03:11:32Z","timestamp":1484709092000},"page":"E244-E252","source":"Crossref","is-referenced-by-count":87,"title":["Mice with hyperbilirubinemia due to Gilbert\u2019s syndrome polymorphism are resistant to hepatic steatosis by decreased serine 73 phosphorylation of PPAR\u03b1"],"prefix":"10.1152","volume":"312","author":[{"suffix":"Jr","given":"Terry D.","family":"Hinds","sequence":"first","affiliation":[{"name":"Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, Ohio;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter 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