2021 Fiscal Year Final Research Report
The study of intra-hepatic cell interation in the development of nonalcoholic fatty liver disease
| Project/Area Number |
19K11737
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 59040:Nutrition science and health science-related
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| Research Institution | University of Tsukuba |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
中川 嘉 富山大学, 学術研究部薬学・和漢系, 教授 (80361351)
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Keywords | 生活習慣病 / 脂質代謝 |
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| Outline of Final Research Achievements |
Liver-specific transcription factor CREBH overexpressing mic were generated using Cre-LoxP system and CRISPR/Cas9 system. This mouse showed severe growth retardation due to growth hormone resistance, demonstrating that CREBH is a factor linking nutritional catabolism and growth retardation.
When CREBH KO mice were fed with an MCD diet, they presented with severe liver damage and hepatitis. From the comprehensive gene expression analysis in the liver, some molecules that cause inflammation were extracted. These factors exacerbated inflammation between hepatic parenchymal cells and nonparenchymal cells. Furthermore, by combining ChIP-seq analysis, it was found that AK2 is novel target gene of CREBH. It is considered that the decrease of AK2 induces an inflammatory reaction by inducing cell death due to the decrease in mitochondrial function.
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| Free Research Field |
栄養学
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| Academic Significance and Societal Importance of the Research Achievements |
CREBHが栄養飢餓の助長と成長阻害を繋ぐ分子であることをマウスレベルで実証したことは、CREBHの機能増強により人工的に栄養飢餓を誘導させられることも示した。この結果はCREBHが肥満の解消させる治療薬開発につなげる可能性を示した。CREBH欠損により肝障害・肝炎を異常なまでに増悪化する。肝臓は様々な細胞で構成されており、肝障害を発症する際には肝臓内の細胞間連関が増悪化に寄与する。この肝機能障害を誘導しうる分泌因子を複数特定し、細胞間連関によるメカニズムの一端を明らかにしたことで、肝炎治療薬開発につながる成果を得た。
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