盐酸小檗碱调节肝肠循环脂质代谢影响胆固醇结石形成的机制研究

Cholesterol gallstone disease is a common disease. Hypersaturation of biliary cholesterol caused by multiple factors involving in multiple pathways is the prerequisite for gallstone formation. However, surgical treatment is the main therapeutic option so far. How to effectively prevent gallstone formation has been one of the key issues in this area. Berberine (BBR) is a common drug and its roles in regulation of lipids and glucose metabolism have been reported in recent years. Our preliminary study showed that BBR could ameliorate gallstone formation in mice fed with lithogenic diet. Very interestingly, the intestinal cholesterol absorption rate decreased as well as biliary cholesterol content. Meanwhile, gut microbiota was remodeled by BBR and the bile acid composition was altered. To further understand the role of BBR in prevention of gallstone formation and the underlying mechanisms, this project will investigate the mechanism of BBR on inhibiting cellular cholesterol absorption of enterocytes, on remodeling of gut microbiota and its regulation of entero-hepatic bile acids metabolism, on the regulation of hepatic cholesterol and bile acid metabolism as well on the regulation of cholesterol homeostasis by influencing arachidonic acid metabolism. The results of this project will provide a novel therapeutic way to prevent gallstone formation and further experimental evidences.

胆囊胆固醇结石病（胆石病）是常见病，其发病机制与多因素多环节所致胆汁胆固醇过饱和有关，目前治疗仍以手术为主。如何有效防治胆石病一直是本领域不断探索的重要研究目标。盐酸小檗碱（Berberine，BBR）是一种常用药物，近年来发现其具有调节血脂、血糖代谢等作用。本课题组开展的预实验结果显示，BBR可抑制小鼠胆石形成，降低小肠胆固醇摄取率、调节肠道菌群并降低胆汁胆固醇饱和度。据此，我们认为，BBR可能通过对胆固醇和胆汁酸在肝肠循环代谢中多环节的调控，降低胆汁胆固醇含量而预防胆石形成。为进一步揭示BBR对胆石的防治作用及潜在分子机制，本项目拟结合动物、细胞及临床研究，分别明确BBR在肠道抑制小肠上皮细胞内胆固醇转运、重塑肠道菌群调节胆汁酸代谢的分子机制；在肝脏直接及经花生四烯酸通路影响肝细胞胆固醇代谢平衡，经肠肝循环多环节调节机制实现其抗胆石形成的效应，进而为胆石病防治提出新的实验依据。

盐酸小檗碱是一种中药制剂，研究显示其具有降低胆固醇作用，但其机制并未完全明确。本研究首先发现BBR具有降低肝脏胆固醇负荷作用，从而缓解胆固醇导致的肝细胞自噬阻滞，这与其抑制cox2酶及前列腺素代谢产物，抑制AKT/mTOR磷酸化从而缓解自噬。本研究还发现肠道菌群代谢物TMAO通过上调肝脏胆固醇转运蛋白ABCG5/G8具有促进胆固醇结石形成的作用。肠道脱硫弧菌及其产物H2S通过肝脏FXR/CYP7A代谢通路，抑制胆汁酸合成，改变胆汁酸成分增加其疏水性促进胆固醇结石形成的机制。本研究结果为胆固醇结石病形成的分子机制提供了新的实验依据。