Regulation of bile acid metabolism by nuclear receptors

核受体对胆汁酸代谢的调节

• 批准号: 15390091
• 负责人: MAKISHIMA Makoto
• 金额: $ 8.7万
• 依托单位: Nihon University (2004-2005)Osaka University (2003)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-15390091/
• 关键词: nuclear receptor; bile acid; plant sterol; LXR; VDR; metabolism; transcription; cholestasis; RXR; 遺伝子; FXR; PXR; リトコール酸; コレステロール; ABCトランスポーター; エルゴステロール

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.

本论文研究了核受体对胆汁酸代谢的调控及其与脂类和维生素代谢的关系，发现了以下新的发现：1.新配体的鉴定（1）通过筛选具有核受体激活作用的甾醇类化合物，发现植物甾醇衍生物具有LXR配体的作用。麦角甾醇衍生物可有效激活LXRα和LXRβ，并选择性诱导小鼠肠道靶基因表达。(2)We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。我们发现了一个新的VDR配体，石胆酸乙酸酯。它选择性地激活了VDR。(3)By通过对胆汁酸受体激活机制的研究，我们发现Na+，K+-ATP酶抑制剂可增强配体依赖性VDR活性。(4)We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作为RXR异源二聚体起作用。我们发现了一个RXR配体，它选择性地激活RXR与孤儿核受体NGFI-B和Nurr 1的异源二聚体。2.基因转录调控我们研究了胆汁酸/脂质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的发生，因此LXR可能介导了膳食脂质信号和细胞增殖机制之间的功能联系。3.体内分析我们通过胆管结扎建立了小鼠胆汁淤积模型，检测胆汁酸受体靶基因的表达，发现肾脏RANKL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骨代谢异常的机制。

项目成果

Induction of intestinal ATP-binding cassette transporter by a phytosterol-derived liver X receptor agonist

植物甾醇衍生的肝脏 X 受体激动剂诱导肠道 ATP 结合盒转运蛋白

• 发表时间: 2003
• 期刊: Journal of Biological Chemistry 278・38
• 作者: Adachi;R.;Shulman;A.I.;Yamamoto;K.;Shimomura;I.;Yamada;S.;Mangelsdorf;D.J.;Makishima;M.;Emi Kaneko
• 通讯作者: Emi Kaneko

Ryutaro Adachi: "Structural determinants for vitamin D receptor response to endocine and xenobiotic signals"Molecular Endocrinology. 18・1. 43-52 (2004)

安达龙太郎：“维生素 D 受体对内分泌和外源信号的反应的结构决定因素”分子内分泌学 18・1（2004 年）。

Regulation of cholesterol and bile acid metabolism by nuclear receptors

核受体对胆固醇和胆汁酸代谢的调节

• 期刊: Journal of Pharmacological Sciences (In press)
• 作者: Iijima;K.;Min-Sun Shin;Soren Warming;Keiko Akagi;Ryutaro Adachi;Makoto Makishima
• 通讯作者: Makoto Makishima

Selective allosteric ligand activation of the retinoid X receptor heterodimaers of NGFI-B and Nurrlc

NGFI-B 和 Nurrlc 类视黄醇 X 受体异二聚体的选择性变构配体激活

• 发表时间: 2005
• 期刊: Biochemical Pharmacology 71・1-2
• 作者: Ryutaro Adachi;Makoto Makishima;Makoto Makishima;Hiroyuki Nakano;Kentaro Morita
• 通讯作者: Kentaro Morita

Regulation of xenobiotic metabolism by xenobiotic receptors and cytochrome P450 enzymes

异生素受体和细胞色素 P450 酶对异生素代谢的调节

• 发表时间: 2005
• 期刊: Nihon University School of Medicine 47・3
• 作者: Ryutaro Adachi;Makoto Makishima;Makoto Makishima;Hiroyuki Nakano;Kentaro Morita;Shigeyuki Uno
• 通讯作者: Shigeyuki Uno