| Project/Area Number |
15390091
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General medical chemistry
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| Research Institution | Nihon University (2004-2005)
Osaka University (2003) |
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Principal Investigator |
MAKISHIMA Makoto Nihon University, School of Medicine, Professor, 医学部, 教授 (70346146)
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| Project Period (FY) |
2003 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥13,600,000 (Direct Cost: ¥13,600,000)
Fiscal Year 2005: ¥4,400,000 (Direct Cost: ¥4,400,000)
Fiscal Year 2004: ¥4,400,000 (Direct Cost: ¥4,400,000)
Fiscal Year 2003: ¥4,800,000 (Direct Cost: ¥4,800,000)
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| Keywords | 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 |
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| Research Abstract |
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 regulation
We 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 analysis
We 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.
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