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Despite sharing common pathological processes, these models exhibit distinct characteristics in their BA pools. The study investigates the impact of hydrophobic BA (<jats:sup>Hpho<\/jats:sup>BA) and hydrophilic BA (<jats:sup>Hphil<\/jats:sup>BA) on CGD development using cytochrome\u2010P450\u20102c70 knockout (C70\u2010KO) mice (mice<jats:sup>C70\u2010KO<\/jats:sup>), genetically modified to resemble humans with a hydrophobic BA pool. All mice<jats:sup>C70\u2010KO<\/jats:sup> fed the WD develop CGD, resembling human cholelithiasis patients, while WD\u2010fed wild\u2010type (WT) mice (mice<jats:sup>WT<\/jats:sup>) show cholesterol\u2010saturated bile but rarely form gallstones. Compared to mice<jats:sup>WT<\/jats:sup>, WD\u2010fed mice<jats:sup>C70\u2010KO<\/jats:sup>\u00a0display caveolae microdomain redistribution in the gallbladder mediated by the\u00a0<jats:sup>Hpho<\/jats:sup>BA, FXR, and miR30c\/e axis, which enhances the Sp1 transcriptional activity of mucin\u20101 (<jats:italic>MUC1<\/jats:italic>) genes through nuclear translocation of protein kinase C\u03b6 (PKC\u03b6). These changes contribute to increased production of pronucleating agents (MUC1 and MUC5ac) and accelerate crystallization of gallbladder cholesterol. The data also suggest that WD\u2010fed mice<jats:sup>C70\u2010KO<\/jats:sup>\u00a0appropriately model human CGD since lithogenic diet\u2010fed mice<jats:sup>WT<\/jats:sup>\u00a0have a larger BA pool that masks the negative effects of gallbladder FXR on CGD development.<\/jats:p>","DOI":"10.1002\/advs.202401956","type":"journal-article","created":{"date-parts":[[2025,2,11]],"date-time":"2025-02-11T09:55:36Z","timestamp":1739267736000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["A Gallbladder\u2010Specific Hydrophobic Bile Acid\u2010FXR\u2010MUC1 Signaling Axis Mediates Cholesterol Gallstone Formation"],"prefix":"10.1002","volume":"12","author":[{"given":"Hongtan","family":"Chen","sequence":"first","affiliation":[{"name":"Division of Gastroenterology the First Affiliated Hospital Zhejiang University School of Medicine  Hangzhou Zhejiang 310002 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