| Project/Area Number |
17390262
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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 |
Metabolomics
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| Research Institution | Shiga University of Medical Science |
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Principal Investigator |
KASHIWAGI Atsunori Shiga University of Medical Science, Undergraduate School of Medicine, Professor (20127210)
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| Co-Investigator(Kenkyū-buntansha) |
MAEGAWA Hiroshi Shiga University of Medical Science, Undergraduate School of Medicine, Associate Professor (00209363)
NISHIO Yoshihiko Shiga University of Medical Science, Undergraduate school of Medicine, Associate Professor (40281084)
MAEDA Shiro RIKEN, SNP, Research Center, Team reader (50314159)
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| Project Period (FY) |
2005 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥16,570,000 (Direct Cost: ¥15,400,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2007: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2006: ¥3,800,000 (Direct Cost: ¥3,800,000)
Fiscal Year 2005: ¥7,700,000 (Direct Cost: ¥7,700,000)
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| Keywords | SREBP-1c / Fructose / Nutrients / RBMX / RBMX / SREBP-1c / 肝細胞 / 遺伝子発現調節 / 代謝症候群 / 果糖反応性遺伝子 / インスリン抵抗性 |
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| Research Abstract |
In rodents a high-fructose diet induces metabolic derangements similar to those in metabolic syndrome. Previously we suggested that in mouse liver an unidentified nuclear protein binding to the region at around -468 by of SREBP-1 c promoter where we found a single nucleotide polymorphism (SNP) plays a key role for the response to high-fructose diet. Here, using MALDI-TOF MASS technique, we identified an X-chromosome-linked RNA binding motif protein (RBMX) as a new candidate molecule. In EMSA, anti-RBMX antibody displaced the bands induced by fructose-feeding. Overexpression or suppression of RBMX on rat hematoma cells regulated the SREBP-1c promoter activity. RBMX may control SREBP-1c expression in mouse liver in response to high-fructose diet.
Furthermore, to elucidate the mechanism by which the protein RBMX activates the SREBP-1c promoter under the influence of a SNP at -468 by of SREBP-1c promoter, we performed yeast one-hybrid and two-hybrid analyses and identified the hypothetical
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gene LOC673353. The nucleotide sequence of LOC673353 is almost identical to a part of 18S ribosomal RNA gene and expressed as mRNA and protein in mouse liver. LOC673353, but not RBMX, directly bound to the promoter region of SREBP-1c gene and recognized the SNP at -468 by of SREBP-1c promoter. Pull-down assay demonstrated that LOC673353 interacted with RBMX. The overexpression of LOC673353 in hepatocytes activates the promoter of SREBP-1c gene depending on the affinity to RBMX and the SNP at -468 bp. Furthermore, RNA interference of LOC673353 specifically inhibited the RBMX-induced promoter activity of SREBP-1c. In mouse liver, the binding of LOC673353 to the SREBP-1c promoter was detected by using chromatin immunoprecipitation assay and the binding to RBMX by using the immunoprecipitation assay. These results clearly indicate that the newly identified LOC673353 directly binds to the SNP region at -468 by of SREBP-1c promoter and regulates SREBP-1c promoter through interaction with RBMX. Less
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