Exosome-derived miR-107 targeting caveolin-1 promotes gallstone progression by regulating the hepatobiliary cholesterol secretion pathway

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.

Caveolin-1; Cholesterol; Exosome; Gallbladder; Gallstone; Risk factor; Treatment; miR-107; microRNA.