2018 Fiscal Year Final Research Report
Study of role of SPRY2/FGF19 in regulation of bile acid synthesis
| Project/Area Number |
15K19611
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Multi-year Fund |
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| Research Field |
Pediatrics
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| Research Institution | Osaka University |
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Principal Investigator |
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| Project Period (FY) |
2015-04-01 – 2019-03-31
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| Keywords | 胆道閉鎖症 / 小児胆汁鬱滞性疾患 / FGF19 |
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| Outline of Final Research Achievements |
We analyzed the regulation of molecules in FGF19 signaling pathways using liver and serum samples from eight biliary atresia (BA) children. CYP7A1 mRNA expression was not inhibited in BA microdissected hepatocyte-enriched tissue (HET) despite high serum bile acid concentrations. The FGF19 protein was synthesized in BA HET, and its serum concentration was elevated. FGFR4 was phosphorylated in BA livers. However, ERK phosphorylation was significantly reduced. We examined SPRY2 expression to determine how the ERK pathway was inactivated downstream of the FGF receptor; the expression was significantly increased in BA HET. FGF19 was increased in BA hepatocytes. By focusing on its regulation in hepatocytes, we showed that the FGF19 pathway did not suppress bile acid synthesis, probably due to an altered mechanism involving upregulated SPRY2 in BA patients.
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| Free Research Field |
小児肝臓学
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| Academic Significance and Societal Importance of the Research Achievements |
肝細胞にクローズアップして解析すると、慢性胆汁鬱滞の状況下にある小児胆道閉鎖症患者の肝細胞においては、SPRY2の発現増加によりERK経路が不活性化することでFGF19経路のCYP7A1 mRNAの適切な発現抑制が起こらず、胆汁酸生合成は抑制されていなかった。このことは胆道閉鎖症における急速な肝硬変、肝不全への進行のメカニズムの一因である可能性がある
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