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Bile salt export pump (BSEP) KO mice are metabolically preconditioned with a hydrophilic BA composition protecting them from cholestasis. We hypothesize that changes in hepatic BA profile and subsequent changes in BA signalling may critically determine the susceptibility to steatohepatitis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Wild\u2010type (WT) and BSEP KO mice were challenged with methionine choline\u2010deficient (MCD) diet to induce steatohepatitis. Serum biochemistry, lipid profiling as well as intestinal lipid absorption were assessed. Markers of inflammation, fibrosis, lipid and BA metabolism were analysed. Hepatic and faecal BA profile as well as serum levels of the BA synthesis intermediate 7\u2010hydroxy\u20104\u2010cholesten\u20103\u2010one (C4) were also investigated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Bile salt export pump KO MCD\u2010fed mice developed less steatosis but more inflammation than WT mice. Intestinal neutral lipid levels were reduced in BSEP KO mice at baseline and under MCD conditions. Faecal non\u2010esterified fatty acid concentrations at baseline and under MCD diet were markedly elevated in BSEP KO compared to WT mice. Serum liver enzymes and hepatic expression of inflammatory markers were increased in MCD\u2010fed BSEP KO animals. PPAR\u03b1 protein levels were reduced in BSEP KO mice. Accordingly, PPAR\u03b1 downstream targets Fabp1 and Fatp5 were repressed, while NF\u03baB subunits were increased in MCD\u2010fed BSEP KO mice. Farnesoid X receptor (FXR) protein levels were reduced in MCD\u2010fed BSEP KO vs WT mice. Hepatic BA profile revealed elevated levels of T\u03b2MCA, exerting FXR antagonistic action, while concentrations of TCA (FXR agonistic function) were reduced.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Presence of hydroxylated BAs result in increased faecal FA excretion and reduced hepatic lipid accumulation. This aggravates development of MCD diet\u2010induced hepatitis potentially by decreasing FXR and PPAR\u03b1 signalling.<\/jats:p><\/jats:sec>","DOI":"10.1111\/liv.14423","type":"journal-article","created":{"date-parts":[[2020,3,6]],"date-time":"2020-03-06T11:50:16Z","timestamp":1583495416000},"page":"1366-1377","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Absence of Bsep\/Abcb11 attenuates MCD diet\u2010induced hepatic steatosis but aggravates inflammation in mice"],"prefix":"10.1111","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0636-1320","authenticated-orcid":false,"given":"Claudia D.","family":"Fuchs","sequence":"first","affiliation":[{"name":"Hans Popper Laboratory of Molecular Hepatology Division of Gastroenterology and Hepatology Department of Internal Medicine III Medical University of Vienna Vienna 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