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AQP3-mediated activation of the AMPK/SIRT1 signaling pathway curtails gallstone formation in mice by inhibiting inflammatory injury of gallbladder mucosal epithelial cells

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  • Ganggang Wang (Creator)
  • Hao ZhangSichuan University, Huazhong University of Science and Technology, Shanghai Children's Medical Center, University of Arizona, Zhongnan Hospital of Wuhan University, Chinese Academy of Sciences, Yunnan Academy of Agricultural Sciences, Shandong University, University of Victoria, Nanyang Technological University, Hubei Academy of Agricultural Sciences, Jiangsu Province Hospital, Heilongjiang Provincial Hospital, South China University of Technology, Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing , China; Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing , China, Northwestern Polytechnical University Xian, Beijing Anzhen Hospital, Department of Pathology, The First Affiliated Hospital of Hainan Medical University, Haikou, China;, Ocean University of China, Shanghai Stomatological Hospital, Inner Mongolia Academy of Agricultural & Animal Husbandry Sciences, China agricultural University, Guangdong University of Petrochemical Technology, Chinese Academy of Medical Sciences & Peking Union Medical College, Guangdong Pharmaceutical University, Wenzhou Medical University, Jilin University, Second Affiliated Hospital of Harbin Medical University, Jinan University, Dalian University of Technology, Fudan University, Nanjing Medical University, Harvard University, Urology Department The Affiliated Qingdao Central Hospital of Qingdao University, The Second Affiliated Hospital of Medical College of Qingdao University Qingdao Shandong China, Ruijin Hospital, Chongqing Medical University, Cornell University, Changhai Hospital, Zhejiang University, Jiangnan University, Second Affiliated Hospital of Nanjing Medical University, Center for Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China., University of Chinese Academy of Sciences, Shanghai Jiao Tong University, Nanjing Agricultural University, Nanchang University, Ruian People's Hospital, Pudong Medical Center, Henan Normal University, First Affiliated Hospital of Harbin Medical University, McGill University, Hunan Agricultural University (Creator)
  • Zhijie Zhou (Creator)
  • Wenzhi Jin (Creator)
  • Xin Zhang (Creator)
  • Zenghui Ma (Creator)
  • Xiaoliang Wang (Creator)

Description

Abstract Background Inflammatory injury of gallbladder mucosal epithelial cells affects the development of cholelithiasis, and aquaporin 3 (AQP3) is an important regulator of inflammatory response. This study reports a mechanistic insight into AQP3 regulating gallstone formation in cholelithiasis based on high-throughput sequencing. Methods A mouse model of cholelithiasis was induced using a high-fat diet, and the gallbladder tissues were harvested for high-throughput sequencing to obtain differentially expressed genes. Primary mouse gallbladder mucosal epithelial cells were isolated and induced with Lipopolysaccharides (LPS) to mimic an in vitro inflammatory injury environment. Cell biological phenotypes were detected by TdT-mediated dUTP Nick-End Labeling (TUNEL) assay, flow cytometry, Cell Counting Kit-8 (CCK-8) assay, and Trypan blue staining. In addition, enzyme linked immunosorbent assay (ELISA) determined the production of inflammatory factors in mouse gallbladder mucosa. Results Whole-transcriptome sequencing data analysis identified 489 up-regulated and 1007 down-regulated mRNAs. Bioinformatics analysis revealed that AQP3 was significantly down-regulated in mice with cholelithiasis. AQP3 might also confer an important role in LPS-induced gallbladder mucosal injury. Overexpression of AQP3 activated the AMPK (adenosine monophosphate-activated protein kinase) / SIRT1 (sirtuin-1) signaling pathway to reduce LPS-induced inflammatory injury of the gallbladder mucosa epithelium, thereby ameliorating gallbladder damage and repressing gallstone formation in mice. Conclusion Data from our study highlight the inhibitory role of AQP3 in gallbladder damage and gallstone formation in mice by reducing inflammatory injury of gallbladder mucosal epithelial cells, which is achieved through activation of the AMPK/SIRT1 signaling pathway.
Date made available2023
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