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

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 (^HphoBA) and hydrophilic BA (^HphilBA) 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 ^HphoBA, 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.