Wang Xinxing, Ma Mingze, Zhu Lichao, Qin Chuan, Shao Shuai, Xu Xianwen, Gao Ruxin, Zhang Zhenhai
Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong Province 250021, China.
Department of Infectious Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong Province 250021, China.
Biochem Pharmacol. 2025 Feb;232:116735. doi: 10.1016/j.bcp.2024.116735. Epub 2024 Dec 24.
Cholesterol gallstone is a disease with high incidence and quality of life. This study aimed to investigate the function of exosome-derived miRNA in gallstone formation and its related molecular mechanism. Exosomes were extracted and isolated from patients with gallbladder stones and age- and gender-matched healthy controls, and exosomal miRNA expression was compared between the two groups. The function of exosomal miR-107 in gallstone formation was evaluated using a lithogenic fed-induced gallstone mouse model. We used a dual luciferase reporter assay to identify the miR-107 target gene. Expression of BSEP and CYP7A1 were detected using Western Blot and immunohistochemical staining to ascertain the role of miR-107 in bile acid transport and cholesterol synthesis. Bile acids, phospholipids, cholesterol and triglycerides were determined with the kit, and cholesterol saturation index was calculated. Liver cholesterol transport-related genes, phospholipid transport-related genes, liver bile salt transport-related genes, sodium-dependent bile acid transporters and organic solute transporters were detected by q-PCR. Exosomal miR-107 high expression was significant in people with gallstones. Inhibitor of miR-107 reduced lithogenic diet-induced gallstone formation in mice. MiR-107 directly inhibited caveolin-1 expression. Inhibition of caveolin-1 reduced the BSEP function. After treatment of miR-107 inhibitor, the expression of BSEP and CYP7A1 was significantly increased compared with gallbladder stones model, but the concentration of bile acid in gallbladder was significantly decreased. miR-107 altered biliary and liver lipid profiles and increased biliary cholesterol saturation index (CSI). Inhibited miR-107 promoted liver homeostasis-related cholesterol and the expression of bile acid transporters. This study revealed that exosome-derived miR-107 promoted gallstone progression by regulating the hepatobiliary cholesterol secretion pathway through targeting caveolin-1.
