A Gallbladder‐Specific Hydrophobic Bile Acid‐FXR‐MUC1 Signaling Axis Mediates Cholesterol Gallstone Formation

Abstract Differences in the distribution of hydrophilic and hydrophobic bile acids (BA) are observed in mouse models of non‐alcoholic fatty liver disease (NAFLD) induced by a high‐fat‐cholesterol “Western‐style” diet (WD), and cholesterol gallstone disease (CGD) induced by a lithogenic diet. Despite sharing common pathological processes, these models exhibit distinct characteristics in their BA pools. The study investigates the impact of hydrophobic BA ( Hpho BA) and hydrophilic BA ( Hphil BA) on CGD development using cytochrome‐P450‐2c70 knockout (C70‐KO) mice (mice C70‐KO ), genetically modified to resemble humans with a hydrophobic BA pool. All mice C70‐KO fed the WD develop CGD, resembling human cholelithiasis patients, while WD‐fed wild‐type (WT) mice (mice WT ) show cholesterol‐saturated bile but rarely form gallstones. Compared to mice WT , WD‐fed mice C70‐KO display caveolae microdomain redistribution in the gallbladder mediated by the Hpho BA, FXR, and miR30c/e axis, which enhances the Sp1 transcriptional activity of mucin‐1 ( MUC1 ) genes through nuclear translocation of protein kinase Cζ (PKCζ). These changes contribute to increased production of pronucleating agents (MUC1 and MUC5ac) and accelerate crystallization of gallbladder cholesterol. The data also suggest that WD‐fed mice C70‐KO appropriately model human CGD since lithogenic diet‐fed mice WT have a larger BA pool that masks the negative effects of gallbladder FXR on CGD development.