Elucidation of the role of glucagon-responsive methyltransferase in hepatic metabolism and tumorigenesis
| Project/Area Number |
19H03713
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (B)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Review Section |
Basic Section 54040:Metabolism and endocrinology-related
|
|---|
| Research Institution | National Center for Global Health and Medicine |
|---|
Principal Investigator |
Matsumoto Michihiro 国立研究開発法人国立国際医療研究センター, 研究所 糖尿病研究センター 分子代謝制御研究部, 部長 (90467663)
|
|---|
| Project Period (FY) |
2019-04-01 – 2022-03-31
|
| Project Status |
Completed (Fiscal Year 2021)
|
| Budget Amount *help |
¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000)
Fiscal Year 2021: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2020: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Fiscal Year 2019: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
|
|---|
| Keywords | メチル化酵素 / グルカゴン / 肝糖新生 / 非アルコール性脂肪性肝疾患 / 肝細胞がん / 遺伝子転写 / エピゲノム / PKA / PGC-1α / 肝癌 / NAFLD / 肝細胞癌 / 肝がん |
|---|
| Outline of Research at the Start |
本研究では、先行研究より同定したグルカゴン応答性メチル化酵素が、肝臓の代謝調節において果たす生理学的役割、およびインスリン抵抗性を呈する肝臓に併存する2型糖尿病・NAFLD/肝癌における病態生理学的役割を分子レベル、個体レベルで明らかにする。また病態モデル動物における肝臓特異的な本酵素の活性制御により、疾患治療標的としての可能性も検証し、画期的な治療法の開発をめざす。
|
| Outline of Final Research Achievements |
In this study, we investigated the role of SETX, of which expression is induced by glucagon in hepatocytes, in the regulation of hepatic gluconeogenesis and tumorigenesis. SETX methylated and activated the acetyltransferase GCN5, activated gluconeogenic program, and promoted hepatic gluconeogenesis. SETX also inhibited the function of a cancer suppressor gene product in a methyltransferase-dependent manner, suppressed cell death upon DNA damage, and promoted hepatocarcinogenesis. Our comprehensive analysis for substrates of this enzyme revealed candidate proteins related to cell proliferation, protein synthesis, cell death, and mitochondrial function. These findings suggest that SETX is a glucagon-responsive promoter of hepatic gluconeogenesis and tumorigenesis，and may regulates other biological processes through the methylation of various proteins.
|
| Academic Significance and Societal Importance of the Research Achievements |
これまで知られていなかった本酵素の肝臓における代謝調節ならびにがん化における機能を、分子メカニズムと共に明らかにした。肝糖新生の亢進は糖尿病の高血糖の主な原因であり、肥満・2型糖尿病モデルマウスの肝臓における本酵素の機能抑制により高血糖が改善したことから、本酵素が糖尿病の治療標的となることを初めて示したと言える。肝がんに関しても本酵素は治療ないしは予防の分子標的となる可能性がある。加えて、NAFL/NASH/肝がん発症モデルの肝臓における本酵素の欠損による腫瘍形成の抑制は脂肪肝、炎症、線維化の改善を伴わなかったことから、この腫瘍抑制効果は肝がんのみならず多様ながんへ応用できる可能性がある。
|
Report
(4 results)
Research Products
(27 results)
-
[Journal Article] tepwise cell fate decision pathways during osteoclastogenesis at single-cell resolution.2021
Author(s)
Tsukasaki M, Huynh NC, Okamoto K, Muro R, Terashima A, Kurikawa Y, Komatsu N, Pluemsakunthai W, Nitta T, Abe T, Kiyonari H, Okamura T, Sakai M, Matsukawa T, Matsumoto M, Kobayashi Y, Penninger JM, Takayanagi H
-
Journal Title
Nat Metab
Volume: 2
Issue: 12
Pages: 1382-1390
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
-
-
-
-
[Journal Article] GCN2 regulates pancreatic β-cell mass by sensing intracellular amino acid levels.2020
Author(s)
Kanno A, Asahara SI, Furubayashi A, Masuda K, Yoshitomi R, Suzuki E, Takai T, Kimura-Koyanagi M, Matsuda T, Bartolome A, Hirota Y, Yokoi N, Inaba Y, Inoue H, Matsumoto M, Inoue K, Abe T, Wei FY, Tomizawa K, Ogawa W, Seino S, Kasuga M, Kido Y.
-
Journal Title
JCI Insight.
Volume: 5
Issue: 9
Pages: 128820-128820
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
-
-
-
-
[Journal Article] EP4 receptor-associated protein (EPRAP) regulates gluconeogenesis in the liver and is associated with hyperglycemia in diabetic mice.2019
Author(s)
5.Higuchi S, Fujikawa R, Nakatsuji M, Yasui M, Ikedo T, Nagata M, Mishima K, Irie K, Matsumoto M, Yokode M, Minami M.
-
Journal Title
Am J Physiol Endocrinol Metab
Volume: 316
Issue: 3
Pages: E410-E417
DOI
Related Report
Peer Reviewed
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
