Regulation of bile acid metabolism by nuclear receptors

我们研究了核受体对胆汁酸代谢的调节及其与脂质和维生素代谢的关系，发现了以下新发现：(1)通过筛选甾醇类化合物对核受体的激活作用，我们发现植物甾醇衍生物可以作为LXR配体。麦角甾醇衍生物可有效激活小鼠肠道中LXRα和LXRβ，并选择性诱导靶基因表达。(2)研究了VDR与石胆酸的构效关系，建立了石胆酸在VDR配体结合口袋中的对接模型。我们发现了一种新的VDR配体，醋酸石胆酸。它选择性地激活了VDR。(3)通过研究胆汁酸受体的激活机制，我们发现Na+， K+- atp酶抑制剂增强了配体依赖性VDR活性。(4)研究了几种RXR配体对RXR异源二聚体活化的影响，因为胆汁酸受体FXR、PXR和VDR是RXR异源二聚体。我们发现了一种RXR配体，它可以选择性地激活具有孤儿核受体NGFI-B和Nurr1.2的RXR异源二聚体。我们研究了胆汁酸/脂敏感核受体与其他转录调控系统之间的串扰，发现LXR抑制β-catenin诱导的转录。由于β-catenin参与肠粘膜细胞增殖和结肠癌发生，LXR可能通过膳食脂质信号和细胞增殖机制介导功能联系。体内分析通过胆管结扎建立小鼠胆汁淤积模型，检测胆汁酸受体靶基因的表达，发现肾脏中RANKL的表达增加。RANKL是VDR靶点，参与骨代谢。这些数据提示了胆汁淤积引起的骨代谢异常的机制。

We investigated regulation of bile acid metabolism by nuclear receptors and its relation to lipid and vitamin metabolisms and found the following novel findings.1.Identification of novel ligands(1)By screening sterol compounds on activation of nuclear receptors, we found that plant sterol derivatives act as LXR ligands. An ergosterol derivative activated LXRα and LXRβ effectively and induced target gene expression selectively in intestine in mice.(2)We investigated the structure-activity relationship between VDR and lithocholic acid and generated a docking model of lithocholic acid in VDR ligand-binding pocket. We found a novel VDR ligand, lithocholic acid acetate. It selectively activated VDR.(3)By investigating the mechanism of activation of bile acid receptors, we found that an inhibitor of Na+, K+-ATPase enhances the ligand-dependent VDR activity.(4)We examined the effect of several RXR ligands on activation of RXR heterodimers, because bile acid receptors, FXR,PXR and VDR, act as RXR heterodimers. We found a RXR ligand that selectively activates RXR heterodimers with orphan nuclear receptors, NGFI-B and Nurr1.2.Gene transcription regulationWe investigated crosstalk between bile acid/lipid-sensing nuclear receptors and other transcription regulation systems, and found that LXR inhibited β-catenin-induced transcription. Since β-catenin is involved in proliferation of intestinal mucosal cells and colon carcinogenesis, LXR may mediate functional connection from dietary lipid signals and cell proliferation mechanism.3.In vivo analysisWe generated a cholestasis model by bile duct ligation in mice, and examined expression of target genes of bile acid receptors, and found that expression of RANKL in kidney was increased. RANKL is a VDR target and is involved in bone metabolism. The data suggest a mechanism of cholestasis-induced abnormality in bone metabolism.