{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T17:57:00Z","timestamp":1791482220910,"version":"4.3.4"},"reference-count":34,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2019,2,17]],"date-time":"2019-02-17T00:00:00Z","timestamp":1550361600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund","doi-asserted-by":"publisher","award":["FWF W1226"],"award-info":[{"award-number":["FWF W1226"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Liver International"],"published-print":{"date-parts":[[2019,11]]},"abstract":"Abstract<\/jats:title>Background and Aims<\/jats:title>Bile acids are now accepted as central signalling molecules for the regulation of glucose, amino acid and lipid metabolism. Adrenal gland cortex cells express the bile acid receptors farnesoid X receptor (FXR<\/jats:styled-content>), the G protein\u2010coupled bile acid receptor (TGR<\/jats:styled-content>5) and the sphingosine\u20101\u2010phosphate receptor 2 (S1PR<\/jats:styled-content>2). We aimed to determine the effects of cholestasis and more specifically of bile acids on cortisol production.<\/jats:p><\/jats:sec>Methods<\/jats:title>FXR<\/jats:styled-content> and TGR<\/jats:styled-content>5 knockout mice and controls were subjected to common bile duct ligation (CBDL<\/jats:styled-content>) or chenodeoxycholic acid (CDCA<\/jats:styled-content>) feeding to model cholestasis. Human adrenocortical H295R cells were challenged with bile acids for mechanistic studies.<\/jats:p><\/jats:sec>Results<\/jats:title>We found that CBDL<\/jats:styled-content> and CDCA<\/jats:styled-content> feeding increased the levels of corticosterone, the rodent equivalent to human cortisol and mRNA<\/jats:styled-content> and protein levels of steroidogenesis\u2010related enzymes in adrenals independent of FXR<\/jats:styled-content> and TGR<\/jats:styled-content>5. Taurine\u2010conjugated CDCA<\/jats:styled-content> (TCDCA<\/jats:styled-content>) significantly stimulated cortisol secretion, phosphorylation of extracellular signal\u2010regulated kinase (ERK<\/jats:styled-content>) and expression of steroidogenesis\u2010related genes in human adrenocortical H295R cells. FXR<\/jats:styled-content> and TGR<\/jats:styled-content>5 agonists failed to induce cortisol secretion in H295R cells. S1PR<\/jats:styled-content>2 inhibition significantly abolished TCDCA<\/jats:styled-content>\u2010induced cortisol secretion, lowered phosphorylation of ERK<\/jats:styled-content> and abrogated enhanced transcription of steroidogenesis\u2010related genes in H295R cells. Likewise, siRNA<\/jats:styled-content> S1PR<\/jats:styled-content>2 treatment reduced the phosphorylation of ERK<\/jats:styled-content> and cortisol secretion. Steroidogenic factor\u20101 (SF<\/jats:styled-content>\u20101) transactivation activity was increased upon TCDCA<\/jats:styled-content> treatment suggesting that bile acid signalling is linked to SF<\/jats:styled-content>\u20101. Treatment with SF<\/jats:styled-content>\u20101 inverse agonist AC<\/jats:styled-content>45594 also reduced TCDCA<\/jats:styled-content>\u2010induced steroidogenesis.<\/jats:p><\/jats:sec>Conclusions<\/jats:title>Our findings indicate that supraphysiological bile acid levels as observed in cholestasis stimulate steroidogenesis via an S1PR<\/jats:styled-content>2\u2010ERK<\/jats:styled-content>\u2010SF<\/jats:styled-content>\u20101 signalling pathway.<\/jats:p><\/jats:sec>","DOI":"10.1111\/liv.14052","type":"journal-article","created":{"date-parts":[[2019,1,21]],"date-time":"2019-01-21T14:29:57Z","timestamp":1548080997000},"page":"2112-2123","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Bile acids increase steroidogenesis in cholemic mice and induce cortisol secretion in adrenocortical H295R cells via S1PR<\/scp>2, ERK<\/scp> and SF<\/scp>\u20101"],"prefix":"10.1111","volume":"39","author":[{"given":"Lei","family":"Liu","sequence":"first","affiliation":[{"name":"Research Unit for Experimental and Molecular Hepatology Division of Gastroenterology and Hepatology Department of Internal Medicine Medical University of Graz Graz Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katrin","family":"Panzitt","sequence":"additional","affiliation":[{"name":"Research Unit for Translational Nuclear Receptor Research in Liver Metabolism Division of Gastroenterology and Hepatology Department of Internal Medicine Medical University of Graz Graz Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Racedo","sequence":"additional","affiliation":[{"name":"Research Unit for Experimental and Molecular Hepatology Division of Gastroenterology and Hepatology Department of Internal Medicine Medical University of Graz Graz 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