Department of Pediatric Surgery, Shandong Provincial Hospital, Shandong University , Jinan, 250021, China.
Liver Gall Bladder and Pancreatic Surgery Ward, Qinghai Red Cross Hospital, Xining, 810001, China.
Appl Biochem Biotechnol. 2024 Aug;196(8):5373-5390. doi: 10.1007/s12010-023-04818-x. Epub 2023 Dec 30.
The abnormal increase of Oddi sphincter pressure and total bile duct pressure may play an important role in the formation of cholesterol stones, but the specific molecular mechanism is still unclear. This study aims to investigate it through in vitro and in vivo experiments. A mouse model of Oddi sphincter dysfunction was constructed by stone-inducing diet. We compared the two groups with PKC-α inhibitor GÖ6976 and PKC-α agonist thymeleatoxin. Oddi sphincter pressure and total bile duct pressure were measured. Biochemical analysis of total cholesterol, bile acid and bilirubin was then conducted. The histopathologic changes of bile duct were observed by HE staining and the ultrastructure of liver cells and surrounding tissues was observed by transmission electron microscopy. Through the above experiments, we found that the change of PKC-α expression may affect the formation process of gallstones. The relationship between PKC-α and ABCB11 was further verified by in vitro and in vivo experiments. Our results suggest that ABCB11 and PKC-α are co-expressed in the tubule membrane of hepatocytes and interact with each other in hepatocytes. The high cholesterol diet further enhances the activation of PKC-α and thus reduces the expression of ABCB11. The formation of cholesterol stones is associated with the down-regulation of ABCB11 expression in the tubule membrane of hepatocytes due to kinase signaling. This is the first study to demonstrate that sphincter of Oddi dysfunction induces gallstones through PKC-α inhibition of ABCB11 expression.
Oddi 括约肌压力和总胆管压力的异常增加可能在胆固醇结石的形成中起重要作用，但具体的分子机制尚不清楚。本研究通过体外和体内实验对此进行了探讨。通过结石诱导饮食构建 Oddi 括约肌功能障碍的小鼠模型。我们比较了两组用 PKC-α 抑制剂 GÖ6976 和 PKC-α 激动剂百里香酚酮处理的结果。测量 Oddi 括约肌压力和总胆管压力。然后进行总胆固醇、胆汁酸和胆红素的生化分析。通过 HE 染色观察胆管的组织病理学变化，通过透射电子显微镜观察肝细胞和周围组织的超微结构。通过上述实验，我们发现 PKC-α 表达的变化可能会影响胆结石的形成过程。通过体外和体内实验进一步验证了 PKC-α 和 ABCB11 之间的关系。我们的结果表明，ABCB11 和 PKC-α 在肝细胞的小管膜中共表达，并在肝细胞中相互作用。高胆固醇饮食进一步增强了 PKC-α 的激活，从而降低了 ABCB11 的表达。由于激酶信号，胆固醇结石的形成与肝细胞小管膜中 ABCB11 表达的下调有关。这是第一项表明 Oddi 括约肌功能障碍通过抑制 PKC-α 表达诱导胆结石形成的研究。
