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...
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Wiley
2025-04-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202401956 |
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| author | Hongtan Chen Xin Jiang Yiqiao Li Honggang Guo Jianguo Wu Sha Li Fengling Hu Guoqiang Xu |
| author_facet | Hongtan Chen Xin Jiang Yiqiao Li Honggang Guo Jianguo Wu Sha Li Fengling Hu Guoqiang Xu |
| author_sort | Hongtan Chen |
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| description | 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 (HphoBA) and hydrophilic BA (HphilBA) on CGD development using cytochrome‐P450‐2c70 knockout (C70‐KO) mice (miceC70‐KO), genetically modified to resemble humans with a hydrophobic BA pool. All miceC70‐KO fed the WD develop CGD, resembling human cholelithiasis patients, while WD‐fed wild‐type (WT) mice (miceWT) show cholesterol‐saturated bile but rarely form gallstones. Compared to miceWT, WD‐fed miceC70‐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 miceC70‐KO appropriately model human CGD since lithogenic diet‐fed miceWT have a larger BA pool that masks the negative effects of gallbladder FXR on CGD development. |
| format | Article |
| id | doaj-art-e73038ecc1264a84892f1d3a646c8550 |
| institution | DOAJ |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-e73038ecc1264a84892f1d3a646c85502025-08-20T03:16:56ZengWileyAdvanced Science2198-38442025-04-011213n/an/a10.1002/advs.202401956A Gallbladder‐Specific Hydrophobic Bile Acid‐FXR‐MUC1 Signaling Axis Mediates Cholesterol Gallstone FormationHongtan Chen0Xin Jiang1Yiqiao Li2Honggang Guo3Jianguo Wu4Sha Li5Fengling Hu6Guoqiang Xu7Division of Gastroenterology the First Affiliated Hospital Zhejiang University School of Medicine Hangzhou Zhejiang 310002 ChinaDivision of Gastroenterology the First Affiliated Hospital Zhejiang University School of Medicine Hangzhou Zhejiang 310002 ChinaDivision of Nephrology Zhejiang Provincial People's Hospital Hangzhou Medical College Affiliated Hospital Hangzhou Zhejiang 310014 ChinaLaboratory of Experimental Animal and Safety Evaluation Zhejiang Academy of Medical Sciences Medical College Hangzhou Zhejiang 310063 ChinaClinical laboratory Zhejiang Provincial People's Hospital Hangzhou Medical College Affiliated Hospital Hangzhou Zhejiang 310014 ChinaDivision of Gastroenterology the First Affiliated Hospital Zhejiang University School of Medicine Hangzhou Zhejiang 310002 ChinaDivision of Gastroenterology the First Affiliated Hospital Zhejiang University School of Medicine Hangzhou Zhejiang 310002 ChinaDivision of Gastroenterology the First Affiliated Hospital Zhejiang University School of Medicine Hangzhou Zhejiang 310002 ChinaAbstract 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 (miceC70‐KO), genetically modified to resemble humans with a hydrophobic BA pool. All miceC70‐KO fed the WD develop CGD, resembling human cholelithiasis patients, while WD‐fed wild‐type (WT) mice (miceWT) show cholesterol‐saturated bile but rarely form gallstones. Compared to miceWT, WD‐fed miceC70‐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 miceC70‐KO appropriately model human CGD since lithogenic diet‐fed miceWT have a larger BA pool that masks the negative effects of gallbladder FXR on CGD development.https://doi.org/10.1002/advs.202401956caveolaecholesterol gallstonefarnesoid X receptorhydrophobic bile acid poolprotein kinase Cζ |
| spellingShingle | Hongtan Chen Xin Jiang Yiqiao Li Honggang Guo Jianguo Wu Sha Li Fengling Hu Guoqiang Xu A Gallbladder‐Specific Hydrophobic Bile Acid‐FXR‐MUC1 Signaling Axis Mediates Cholesterol Gallstone Formation Advanced Science caveolae cholesterol gallstone farnesoid X receptor hydrophobic bile acid pool protein kinase Cζ |
| title | A Gallbladder‐Specific Hydrophobic Bile Acid‐FXR‐MUC1 Signaling Axis Mediates Cholesterol Gallstone Formation |
| title_full | A Gallbladder‐Specific Hydrophobic Bile Acid‐FXR‐MUC1 Signaling Axis Mediates Cholesterol Gallstone Formation |
| title_fullStr | A Gallbladder‐Specific Hydrophobic Bile Acid‐FXR‐MUC1 Signaling Axis Mediates Cholesterol Gallstone Formation |
| title_full_unstemmed | A Gallbladder‐Specific Hydrophobic Bile Acid‐FXR‐MUC1 Signaling Axis Mediates Cholesterol Gallstone Formation |
| title_short | A Gallbladder‐Specific Hydrophobic Bile Acid‐FXR‐MUC1 Signaling Axis Mediates Cholesterol Gallstone Formation |
| title_sort | gallbladder specific hydrophobic bile acid fxr muc1 signaling axis mediates cholesterol gallstone formation |
| topic | caveolae cholesterol gallstone farnesoid X receptor hydrophobic bile acid pool protein kinase Cζ |
| url | https://doi.org/10.1002/advs.202401956 |
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