Analysis of metabolic diseases targeting nutrient complex associated inflammation caused from enterohepatic circulation
Project/Area Number |
16H03253
|
Research Category |
Grant-in-Aid for Scientific Research (B)
|
Allocation Type | Single-year Grants |
Section | 一般 |
Research Field |
Applied health science
|
Research Institution | University of Tsukuba |
Principal Investigator |
Nakagawa Yoshimi 筑波大学, 国際統合睡眠医科学研究機構, 准教授 (80361351)
|
Co-Investigator(Kenkyū-buntansha) |
島野 仁 筑波大学, 医学医療系, 教授 (20251241)
松坂 賢 筑波大学, 医学医療系, 教授 (70400679)
|
Project Period (FY) |
2016-04-01 – 2020-03-31
|
Project Status |
Completed (Fiscal Year 2019)
|
Budget Amount *help |
¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000)
Fiscal Year 2019: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2018: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
Fiscal Year 2017: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Fiscal Year 2016: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
|
Keywords | 腸肝循環 / CREBH / SREBP / CRISPR/Cas9システム / 動脈硬化 / 非アルコール性脂肪肝 / 生活習慣病 / 肝がん / 慢性炎症 / 脂質代謝 / CRISPR/Cas9 / FGF21 / 遺伝子発現 / 脂質 / 糖尿病 / 栄養学 |
Outline of Final Research Achievements |
We clarified that the transcription factor CREBH could contribute to the therapeutic strategy of lifestyle-related diseases. CREBH-deficient mice developed high-fat diet-induced abnormal fatty liver, hepatitis, and small intestine structural abnormalities, and then exacerbated these diseases due to abnormal nutrition metabolism. Furthermore, we clarified that CREBH deficiency induces atherosclerosis and liver cancer, which are terminal images of lifestyle-related diseases. Furthermore, we newly generated tissue-specific CREBH overexpression / deficiency mice by creating genetically modified mice using the CRISPR / Cas9 system. Non-alcoholic fatty liver and arteriosclerosis were aggravated in even tissue-specific KO mice of the liver and small intestine. In this study, we clarified that CREBH plays a crucial role in the regulation of nutrient metabolism and nutrient absorption in the liver and small intestine, respectively, and is greatly involved in lifestyle-related diseases.
|
Academic Significance and Societal Importance of the Research Achievements |
CREBHは小胞体ストレスに応答し、炎症反応を惹起させるという報告があった。しかしながら、我々の研究からCREBHは実際には炎症を抑えるとともに、生活習慣病改善ホルモンFGF21を介し病態を改善させる新規の生活習慣病改善に寄与する転写因子であることを明らかにした。CREBHは脂質代謝の改善にも大きく関連し、すでに治療標的となっているPPARαの活性を制御することを見出している。CREBH KOマウスではPPARα活性化薬(フィブラート))による脂質代謝改善効果が失われる。フィブラートで治療できない脂質異常症の新たな治療標的としてCREBHで有効であることを示した。
|
Report
(5 results)
Research Products
(20 results)
-
-
-
-
-
[Journal Article] Epigenetic modulation of Fgf21 in the perinatal mouse liver ameliorates diet-induced obesity in adulthood2018
Author(s)
X Yuan, K Tsujimoto, K Hashimoto, K Kawahori, N Hanzawa, M Hamaguchi, T Seki, M Nawa, T Ehara, Y Kitamura, I Hatada, M Konishi, N Itoh, Y Nakagawa, H Shimano, T Takai-Igarashi, Y Kamei, Y Ogawa.
-
Journal Title
Nature Communications
Volume: 9
Issue: 1
Pages: 636-636
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
-
-
-
[Journal Article] The selective PPARα modulator K-877 efficiently activates the PPARα pathway and improves lipid metabolism in mice2017
Author(s)
Takei K, Han SI, Murayama Y, Satoh A, Oikawa F, Ohno H, Osaki Y, Matsuzaka T, Sekiya M, Iwasaki H, Yatoh S, Yahagi N, Suzuki H, Yamada N, Nakagawa Y, Shimano H.
-
Journal Title
Journal of Diabetes Investigation
Volume: in press
Issue: 4
Pages: 446-452
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
-
[Journal Article] CREB3L3 controls fatty acid oxidation and ketogenesis in synergy with PPARα.2016
Author(s)
Nakagawa Y, Satoh A, Tezuka H, Han SI, Takei K, Iwasaki H, Yatoh S, Yahagi N, Suzuki H, Iwasaki Y, Sone H, Matsuzaka T, Yamada N, Shimano H.
-
Journal Title
Sci Rep.
Volume: 6
Issue: 1
Pages: 39182-39182
DOI
NAID
Related Report
Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
-
[Journal Article] Intestinal CREBH overexpression prevents high-cholesterol diet-induced hypercholesterolemia by reducing Npc1l1 expression.2016
Author(s)
5.Kikuchi T, Orihara K, Oikawa F, Han SI, Kuba M, Okuda K, Satoh A, Osaki Y, Takeuchi Y, Aita Y, Matsuzaka T, Iwasaki H, Yatoh S, Sekiya M, Yahagi N, Suzuki H, Sone H, Nakagawa Y, Yamada N, Shimano H.
-
Journal Title
Molecular Metabolism
Volume: 5
Pages: 1092-1102
NAID
Related Report
Peer Reviewed / Open Access / Acknowledgement Compliant
-
[Journal Article] Hyperlipidemia and hepatitis in liver-specific CREB3L3 knockout mice generated using a one-step CRISPR/Cas9 system.2016
Author(s)
Nakagawa Y, Oikawa F, Ohno H, Yagishita Y, Satoh A, Osaki Y, Takei K, Kikuchi T, Song-iee H, Mizuno S. Matsuzaka T, Iwasaki H, Kobayashi K, Yatoh S, Yahagi N, Suzuki H, Sone H, Takahashi S, Yamada N, Shimano H.
-
Journal Title
Sci Rep.
Volume: 6
Issue: 1
Pages: 27857-27857
DOI
NAID
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
-
-
-
-
-
-
-
-
-