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In the presence of low-function genetic <jats:italic>UGT1A<\/jats:italic> variants fibrosis development is increased in various diseases. This study aimed to examine the role of common <jats:italic>UGT1A<\/jats:italic> polymorphisms in NASH. Therefore, <jats:italic>htgUGT1A<\/jats:italic>-WT mice and <jats:italic>htgUGT1A<\/jats:italic>-SNP mice (carrying a common human haplotype present in 10% of the white population) were fed a high-fat Paigen diet for 24 weeks. Serum aminotransferase activities, hepatic triglycerides, fibrosis development and <jats:italic>UGT1A<\/jats:italic> expression were assessed. Microscopic examination revealed higher hepatic fat deposition and a significant induction of <jats:italic>UGT1A<\/jats:italic> gene expression in <jats:italic>htgUGT1A<\/jats:italic>-WT mice. In agreement with these observations, lower serum aminotransferase activities and lower expression levels of fibrosis-related genes were measured in <jats:italic>htgUGT1A<\/jats:italic>-SNP mice. This was accompanied by reduced PPAR\u03b1 protein levels in <jats:italic>htgUGT1A<\/jats:italic>-WT but not in SNP mice. Our data demonstrate a protective effect of a <jats:italic>UGT1A<\/jats:italic> SNP haplotype, leading to milder hepatic steatosis and NASH. Higher PPAR\u03b1 protein levels in animals with impaired UGT1A activity are the likely result of reduced glucuronidation of ligands involved in PPAR\u03b1-mediated fatty acid oxidation and may lead to the observed protection in <jats:italic>htgUGT1A<\/jats:italic>-SNP mice.<\/jats:p>","DOI":"10.1038\/s41598-020-65481-4","type":"journal-article","created":{"date-parts":[[2020,5,26]],"date-time":"2020-05-26T10:02:38Z","timestamp":1590487358000},"update-policy":"http:\/\/dx.doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["A Gilbert syndrome-associated haplotype protects against fatty liver disease in humanized transgenic mice"],"prefix":"10.1038","volume":"10","author":[{"given":"Steffen","family":"Landerer","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandra","family":"Kalthoff","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefan","family":"Paulusch","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian P.","family":"Strassburg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2020,5,26]]},"reference":[{"key":"65481_CR1","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1111\/j.1751-2980.2010.00469.x","volume":"12","author":"AJ McCullough","year":"2011","unstructured":"McCullough, A. 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