维生素D受体在胆固醇结石形成过程中的作用及机制研究

胆结石是消化系统常见病症。胆固醇结石是胆结石的主要类型，受胆固醇平衡、胆汁含水量等因素的调节。近年研究表明，维生素D受体（VDR）可调节肝纤维化、胆汁淤积性肝损伤等病理生理过程，但其在胆固醇结石形成过程中的作用及机制尚不明确。我们前期发现：临床胆结石患者25-羟维生素D3平均水平较对照组低；致结石饲料喂养的肝脏VDR基因敲除小鼠和VD缺乏致结石饲料喂养的小鼠均较各自对照组更易形成胆固醇结石，肝脏胆固醇平衡及水转运相关基因表达均有改变，提示VDR可能通过影响胆固醇平衡和水转运调节胆固醇结石的形成。本项目将利用胆固醇结石小鼠模型、类器官培养技术、细胞单层模型等，研究VDR在胆固醇结石形成过程中的作用；通过体内外实验阐明VDR对肝脏胆固醇平衡、水转运的调节作用及相关机制；临床标本分析血清25-羟维生素D3水平与血清胆固醇水平、胆固醇结石形成的相关性，为胆固醇结石的防治提供新的理论依据和治疗策略。

Gallstone is a common digestive system disease. Cholesterol calculus, the major type of gallstone, is regulated by cholesterol balance, bile water content and so on. Recent studies have shown that vitamin D receptor (VDR) could regulate several pathophysiological processes such as liver fibrosis, cholestasis liver injury and so on. However, the role of VDR in the formation of cholesterol calculus remains elusive. We previously found that patients with cholesterol calculus got lower 25-hydroxyvitamin D3 level in serum. Besides, we found that VDR liver-specific knockout mice and vitamin D deficiency plus calculus-induced feed mice were more likely to form cholesterol calculus. Further, we found the expressions of cholesterol metabolism balance and water transport regulation related genes were all altered in the liver of VDR knockout mice and vitamin D deficiency plus calculus-induced feed mice. These results revealed that VDR may regulate the formation of cholesterol calculus by affecting cholesterol balance and water transport. We are going to systematically study the role of VDR in the formation of cholesterol calculus by utilizing the cholesterol calculus mice models, organoid culture techniques, cell monolayer models and so on. Besides, relevant experiments are conducted to elucidate the role and mechanism of VDR on cholesterol balance and water transport regulation in vivo and in vitro. In addition, we are going to analyse the correlation between serum 25-hydroxyvitamin D3 level, serum cholesterol level and cholesterol calculus formation, intending to provide the new theoretical basis and therapeutic strategy for the prevention and treatment of cholesterol calculus.