{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T11:46:03Z","timestamp":1784547963317,"version":"3.55.0"},"reference-count":32,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2022,10,15]],"date-time":"2022-10-15T00:00:00Z","timestamp":1665792000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Deutsche Forschungsgemeinschaft (DFG)","award":["Project-ID 424957847\u2014TRR 296\/1"],"award-info":[{"award-number":["Project-ID 424957847\u2014TRR 296\/1"]}]},{"name":"Robert Bosch Foundation","award":["Project-ID 424957847\u2014TRR 296\/1"],"award-info":[{"award-number":["Project-ID 424957847\u2014TRR 296\/1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Women are more prone to develop either hypothyroidism or cholesterol gallstones than men. However, a male predominance in cholesterol gallstones under hypothyroidism was reported. Recently, a novel pathogenic link between thyroid hormone (TH) deficiency and cholesterol gallstones has been described in male mice. Here, we investigate if TH deficiency impacts cholesterol gallstone formation in females by the same mechanism. Three-month-old C57BL\/6J mice were randomly divided into a control, a TH deficient, a lithogenic, and a lithogenic + TH deficient group and diet-treated for two, four, and six weeks. Gallstone prevalence, liver function tests, bile composition, hepatic gene expression, and gallbladder aquaporin expression and localization were investigated. Cholesterol gallstones were observed in lithogenic + TH deficient but not lithogenic only female mice. Diminished hydrophilicity of primary bile acids due to decreased gene expression of hepatic detoxification phase II enzymes was observed. A sex-specific expression and localization of hepatobiliary aquaporins involved in transcellular water and glycerol permeability was observed under TH deficient and lithogenic conditions. TH deficiency promotes cholesterol gallstone formation in female C57BL\/6J mice by the same mechanism as observed in males. However, cholesterol gallstone prevalence was lower in female than male C57BL\/6J mice. Interestingly, the sex-specific expression and localization of hepatobiliary aquaporins could protect female C57BL\/6J mice to cholestasis and could reduce biliary water transport in male C57BL\/6J mice possibly contributing to the sex-dependent cholesterol gallstone prevalence under TH deficiency.<\/jats:p>","DOI":"10.3390\/ijms232012355","type":"journal-article","created":{"date-parts":[[2022,10,17]],"date-time":"2022-10-17T02:29:46Z","timestamp":1665973786000},"page":"12355","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Hepatobiliary Thyroid Hormone Deficiency Impacts Bile Acid Hydrophilicity and Aquaporins in Cholestatic C57BL\/6J Mice"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5341-2066","authenticated-orcid":false,"given":"Irina","family":"Kube","sequence":"first","affiliation":[{"name":"Department of Endocrinology, Diabetes and Metabolism and Clinical Chemistry\u2014Division of Laboratory Research, University of Duisburg-Essen, Hufelandstra\u00dfe 55, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuela","family":"Kowalczyk","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Diabetes and Metabolism and Clinical Chemistry\u2014Division of Laboratory Research, University of Duisburg-Essen, Hufelandstra\u00dfe 55, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0823-9027","authenticated-orcid":false,"given":"Ute","family":"Hofmann","sequence":"additional","affiliation":[{"name":"Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of T\u00fcbingen, Auerbachstra\u00dfe 112, 70376 Stuttgart, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0695-3403","authenticated-orcid":false,"given":"Ahmed","family":"Ghallab","sequence":"additional","affiliation":[{"name":"Leibniz Research Centre for Working Environment and Human Factors, Department of Toxicology\/Systems Toxicology, Ardeystra\u00dfe 67, 44139 Dortmund, Germany"},{"name":"Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena 83523, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan Georg","family":"Hengstler","sequence":"additional","affiliation":[{"name":"Leibniz Research Centre for Working Environment and Human Factors, Department of Toxicology\/Systems Toxicology, Ardeystra\u00dfe 67, 44139 Dortmund, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dagmar","family":"F\u00fchrer","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Diabetes and Metabolism and Clinical Chemistry\u2014Division of Laboratory Research, University of Duisburg-Essen, Hufelandstra\u00dfe 55, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denise","family":"Zwanziger","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Diabetes and Metabolism and Clinical Chemistry\u2014Division of Laboratory Research, University of Duisburg-Essen, Hufelandstra\u00dfe 55, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,15]]},"reference":[{"key":"ref_1","first-page":"919","article-title":"Association between common bile duct stones and treated hypothyroidism","volume":"47","author":"Inkinen","year":"2000","journal-title":"Hepatogastroenterology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"5530","DOI":"10.3748\/wjg.v11.i35.5530","article-title":"Association between thyroid function and gallstone disease","volume":"11","author":"Volzke","year":"2005","journal-title":"World J. 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