ChREBP regulates blood glucose level via the expression of GLUT2

• Project/Area Number: 16K01820
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Applied health science
• Research Institution: Health Sciences University of Hokkaido (2018); Kobe University (2016-2017)
• Principal Investigator: Nakagawa Tsutomu 北海道医療大学, 薬学部, 准教授 (50722063)
• Research Collaborator: UYEDA kosaku ; SAKIYAMA haruhiko
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: ChREBP / GLUT2 / 糖尿病

Outline of Final Research Achievements

ChREBP KO mice showed a decrease in GLUT2 mRNA expression levels in all tissues, except the kidney, compared to the wild type mice. Next, to investigate whether ChREBP binds to the active promoter region of GLUT2, a series of reporter plasmids were constructed, each with a 500 bp insert, located 2.0 kb upstream and up to 500 bp downstream of the transcription start site of GLUT2 gene. The promoter activities of ChREBP were measured in HepG2 cells and not all reporter vectors used in this study demonstrated active promoter-binding interactions. Furthermore, experiments using ChREBP-overexpressed stable cell line, under low glucose condition, showed no correlation between mRNA level of GLUT2 and protein level of ChREBP. These results suggest that ChREBP did not regulate GLUT2 expression directly, but that glucose metabolite(s), which were increased in cells by ChREBP activation, might be involved in the regulation of GLUT2 expression.

Academic Significance and Societal Importance of the Research Achievements

GLUT2の発現量がChREBP KOマウスの様々な臓器において減少したことから、ChREBPがGLUT2の発現を制御していることが明らかとなった。この結果は、ChREBPを標的とした血糖降下薬の開発につながると考えられるため、糖尿病治療に新たな選択肢を加えることができるという点において社会的意義は大きいと考えられる。また、本研究によりChREBPは血糖調節機能を有することが明らかとなり、これまでに明らかになっている生理機能であるグルコース代謝と脂質合成の他に、血糖調節機能というChREBPの新たな生理機能を明らかにしたという点において学術的意義も高いと考えられる。

Research Products

• [Int'l Joint Research] UT Southwestern Medical Center(米国)
• [Journal Article] Association of Expression Levels or Activation Status of STAT3 with Treatment Outcomes of Sunitinib in Patients with Renal Cell Carcinoma. (2018)
  • Author(s): Yamamoto K., Hara T., Nakagawa T., Hirai M., Miyake H., Fujisawa M., Yano I.
  • Journal Title: Targeted Oncology Volume: 13 Issue: 3 Pages: 371-378
  • DOI: 10.1007/s11523-018-0563-4
  • NAID: 120006649622
  • Peer Reviewed
• [Journal Article] Prostaglandin E1 reduces the keratinocyte toxicity of sorafenib by maintaining signal transducer and activator of transcription 3 (STAT3) activity and enhancing the cAMP response element binding protein (CREB) activity. (2017)
  • Author(s): Shichiri H., Yamamoto K., Tokura M., Ishida T., Uda A., Bito T., Nishigori C., Nakagawa T., Hirano T., Yano I., Hirai M.
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 485 Issue: 2 Pages: 227-233
  • DOI: 10.1016/j.bbrc.2017.02.107
  • NAID: 120006733140
  • Peer Reviewed
• [Journal Article] Association of Single Nucleotide Polymorphisms in <i>STAT3</i>, <i>ABCB1</i>, and <i>ABCG2</i> with Stomatitis in Patients with Metastatic Renal Cell Carcinoma Treated with Sunitinib: A Retrospective Analysis in Japanese Patients (2017)
  • Author(s): Watanabe A., Yamamoto K., Ioroi T., Hirata S., Harada K., Miyake H., Fujisawa M., Nakagawa T., Yano I., Hirai M.
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 40 Issue: 4 Pages: 458-464
  • DOI: 10.1248/bpb.b16-00875
  • NAID: 130005530145
  • ISSN: 0918-6158, 1347-5215
  • Peer Reviewed
• [Journal Article] Compatibility and Stability of Nab-Paclitaxel in Combination with Other Drugs. (2017)
  • Author(s): Mizuta N., Nakagawa T., Yamamoto K., Nishioka T., Kume M., Makimoto H., YANO I., Minami H., Hirai M.
  • Journal Title: Kobe Journal of Medical Sciences Volume: 63 Pages: 9-16
  • NAID: 120006329054
  • Peer Reviewed
• [Journal Article] Effects of Ascorbyl-2-phosphate Magnesium on Human Keratinocyte Toxicity and Pathological Changes by Sorafenib (2017)
  • Author(s): Yamamoto K., Shichiri H., Ishida T., Kaku K., Nishioka T., Kume M., Makimoto H., Nakagawa T., Hirano T., Bito T., Nishigori C., Yano I., Hirai M.
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 40 Issue: 9 Pages: 1530-1536
  • DOI: 10.1248/bpb.b17-00386
  • NAID: 130006038784
  • ISSN: 0918-6158, 1347-5215
  • Peer Reviewed
• [Journal Article] シグナル伝達因子に起因する間質性肺炎発症メカニズム (2017)
  • Author(s): 山本和宏，中川勉，矢野育子，平井みどり
  • Journal Title: BIO Clinica Volume: 6 Pages: 121-125
• [Journal Article] 転写因子ChREBPを標的とした生活習慣病の予防法及び治療薬の開発 (2017)
  • Author(s): 崎山晴彦，中川勉，江口裕伸，吉原大作，藤原範子，鈴木敬一郎
  • Journal Title: 細胞 Volume: 49 Pages: 81-84
  • Acknowledgement Compliant
• [Journal Article] Metabolite Regulation of Nuclear Localization of Carbohydrate-response Element-binding Protein (ChREBP): ROLE OF AMP AS AN ALLOSTERIC INHIBITOR (2016)
  • Author(s): Sato S, Jung H, Nakagawa T, Pawlosky R, Takeshima T, Lee WR, Sakiyama H, Laxman S, Wynn RM, Tu BP, MacMillan JB, De Brabander JK, Veech RL, Uyeda K
  • Journal Title: Journal of Biological Chemistry Volume: 291 Issue: 20 Pages: 10515-10527
  • DOI: 10.1074/jbc.m115.708982
  • Peer Reviewed / Int'l Joint Research
• [Presentation] ChREBP欠損マウスが有する抗肥満作用の検討 (2018)
  • Author(s): 崎山 晴彦, 中川 勉, 井上 美奈子, 江口 裕伸, 吉原 大作, 藤原 範子, 鈴木 敬一郎
  • Organizer: 第91回日本生化学会大会
• [Presentation] Carbohydrate response element-binding protein (ChREBP)の活性制御に及ぼすO-GlcNAc修飾の影響 (2017)
  • Author(s): 中川勉，崎山晴彦，山本和宏，藤原範子，鈴木敬一郎，平井みどり
  • Organizer: 第89回日本生化学会大会
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2017-09-25
• [Presentation] Association of Single Nucleotide Polymorphisms in STAT3, ABCB1, and ABCG2 with Stomatitis in Patients with Metastatic Renal Cell Carcinoma Treated with Sunitinib: A Retrospective Analysis in Japanese Patients (2017)
  • Author(s): Watanabe A, Yamamoto K, Ioroi T, Hirata S, Harada K, Miyake H, Fujisawa M, Nakagawa T, Yano I, Hirai M
  • Organizer: The 5th International Symposium of Training Plan for Oncology Professionals
  • Place of Presentation: シェラトン都ホテル大阪（大阪府大阪市）
  • Year and Date: 2017-03-11
  • Int'l Joint Research
• [Presentation] ChREBPのグルコース濃度依存的なDNA結合はO-GlcNAc修飾により制御される (2017)
  • Author(s): 中川勉、吉村友希、崎山晴彦、中川孝俊、山本和宏、矢野育子、藤原範子、朝日通雄、鈴木敬一郎、平井みどり
  • Organizer: 第64回日本生化学会近畿支部例会
• [Presentation] 転写因子ChREBP欠損マウスにおける抗肥満効果 (2017)
  • Author(s): 崎山晴彦、井上美奈子、中川勉、江口裕伸、吉原大作、藤原範子、鈴木敬一郎
  • Organizer: ConBio2017
• [Presentation] エイコサペンタエン酸（EPA）が血清中性脂肪を低下させる分子メカニズムの解明 (2017)
  • Author(s): 中川勉，崎山晴彦，山本和宏，藤原範子，鈴木敬一郎，平井みどり
  • Organizer: 第63回日本生化学会近畿支部例会
  • Place of Presentation: 神戸薬科大学（兵庫県神戸市）
• [Presentation] 不飽和脂肪酸が血清中性脂肪を低下させる分子メカニズムの解明：ChREBPの抑制機構の解明 (2017)
  • Author(s): 中川勉
  • Organizer: 第16回 油脂優秀論文賞受賞講演会
  • Place of Presentation: 奈良女子大学（奈良県奈良市）
• [Remarks] 北海道医療大学 薬剤学（製剤学）研究内容
  • URL: http://www.hoku-iryo-u.ac.jp/~siba/research.html
• [Remarks] 神戸大学大学院医学研究科 薬物動態学・薬剤学分野
  • URL: http://www.med.kobe-u.ac.jp/yakudo/
• [Remarks] 神戸大学病院薬剤部ホームページ
  • URL: http://www.hosp.kobe-u.ac.jp/yakuzai/Pharm/index1.htm