Elucidation of the mechanisms underlying n-3 polyunsaturated fatty acids mediated degradation of ChREBP

• Project/Area Number: 26750041
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Eating habits
• Research Institution: Kobe University
• Principal Investigator: NAKAGAWA TSUTOMU 神戸大学, 医学(系)研究科(研究院), 講師 (50722063)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2014: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: ChREBP / n-3系脂肪酸 / SUMO

Outline of Final Research Achievements

n-3 polyunsaturated fatty acids (PUFA) can reduce plasma triglyceride (TG) level. However, the underlying mechanism of plasma TG reduction remains unclear. Carbohydrate response element-binding protein (ChREBP) is a transcription factor responsible for the coordinated metabolism of carbohydrate and fat synthesis. It was reported that the inhibition of ChREBP in leptin-deficient mice improved plasma TG level. Therefore, it was suggested that ChREBP could be a protein affected by n-3 PUFA, which was involved in reducing plasma TG level. In this study, it was shown that n-3 PUFA could promote the degradation of ChREBP. Moreover, it was found that ChREBP was degraded via the autophagy-lysosomal pathway. The inhibitory effect on ChREBP activity by n-3 PUFA disappeared when the degradation of ChREBP was inhibited by chloroquine treatment. These results suggested that n-3 PUFA promoted the degradation of ChREBP by inducing autophagy, resulting in reduction of plasma TG level.

Research Products

• [Int'l Joint Research] UT Southwestern Medical Center(米国)
• [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 W. R., Sakiyama H., Laxman S., Wynn R. M., Tu B., MacMillan J. B., De Brabander J. K., Veech R. L., Uyeda K.
  • Journal Title: Journal of Biological Chemistry Volume: in press
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] STAT3 polymorphism rs4796793 may be a predictive factor of tumor response to multiple tyrosine kinase inhibitors in metastatic renal cell carcinoma in Japanese population. (2016)
  • Author(s): Yamamoto K., Ioroi T., Kanaya K., Shinomiya K., Komoto S., Hirata S., Harada K., Watanabe A., Suno M., Nishioka T., Kume M., Makimoto H., Nakagawa T., Hirano T., Miyake H., Fujisawa M., Hirtai M.
  • Journal Title: Medical Oncology Volume: 33 Issue: 3 Pages: 24-24
  • DOI: 10.1007/s12032-016-0733-0
  • Peer Reviewed / Open Access
• [Journal Article] Association of Single Nucleotide Polymorphisms in STAT3 with Hand-Foot Skin Reactions in Patients with Metastatic Renal Cell Carcinoma Treated with Multiple Tyrosine Kinase Inhibitors: A Retrospective Analysis in Japanese Patients. (2016)
  • Author(s): Yamamoto K., Shinomiya K., Ioroi T., Hirata S., Harada K., Suno M., Nishioka T., Kume M., Makimoto H., Nakagawa T., Hirano T., Bito T., Nishigori C., Miyake H., Fujisawa M., Hirai M.
  • Journal Title: Targeted Oncology Volume: 11 Issue: 1 Pages: 93-99
  • DOI: 10.1007/s11523-015-0382-9
  • Peer Reviewed
• [Journal Article] Induction of epithelial-mesenchymal transition via activation of epidermal growth factor receptor contributes to sunitinib resistance in human renal cell carcinoma cell lines. (2015)
  • Author(s): Mizumoto A., Yamamoto K., Nakayama Y., Takara K., Nakagawa T., Hirano T., Hirai M.
  • Journal Title: Journal of Pharmacology and Experimental Therapeutics Volume: 355 Issue: 2 Pages: 152-158
  • DOI: 10.1124/jpet.115.226639
  • Peer Reviewed
• [Journal Article] Apoptotic Effects of the Extracts of Cordyceps militaris via Erk Phosphorylation in a Renal Cell Carcinoma Cell Line. (2015)
  • Author(s): Yamamoto K., Shichiri H., Uda A., Yamashita K., Nishioka T., Kume M., Makimoto H., Nakagawa T., Hirano T., Hirai M.
  • Journal Title: Phytotherapy Research Volume: 25 Issue: 5 Pages: 707-713
  • DOI: 10.1002/ptr.5305
  • Peer Reviewed
• [Journal Article] Association of toxicity of sorafenib and sunitinib for human keratinocytes with inhibition of signal transduction and activator of transcription 3 (STAT3). (2014)
  • Author(s): 2.Yamamoto K., Mizumoto A., Nishimura K., Uda A., Mukai A., Yamashita K., Kume M., Makimoto H., Bito T., Nishigori C., Nakagawa T., Hirano T., Hirai M.
  • Journal Title: PLoS One Volume: 9 Issue: 7 Pages: e102110-e102110
  • DOI: 10.1371/journal.pone.0102110
  • NAID: 120005465541
  • Peer Reviewed / Open Access
• [Presentation] Carbohydrate response element-binding protein (ChREBP)の活性制御に及ぼす核移行/核外搬出 シグナルの影響 (2015)
  • Author(s): 中川 勉、吉村 友希、崎山 晴彦、山本 和宏、藤原 範子、 鈴木 敬一郎、平井 みどり
  • Organizer: BMB2015
  • Place of Presentation: 神戸国際会議場
  • Year and Date: 2015-12-03
• [Presentation] ChREBP-βの活性化機構の解明 (2015)
  • Author(s): 吉村友希、中川勉、崎山晴彦、山本和宏、江口裕伸、藤原範子、平野剛、鈴木 敬一郎、平井みどり
  • Organizer: 日本薬学会第135年会
  • Place of Presentation: 神戸学院大学（兵庫県・神戸市）
  • Year and Date: 2015-03-25 – 2015-03-28
• [Presentation] 新規mTORC1結合因子P110の栄養感知システムとしての生理機能解析 (2014)
  • Author(s): 七里博章、山本和宏、中川 勉、平野 剛、平井 みどり
  • Organizer: 第37回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜（神奈川県・横浜市）
  • Year and Date: 2014-11-25 – 2014-11-27
• [Presentation] ChREBPと14-3-3の結合に影響を与える代謝物の同定 (2014)
  • Author(s): 中川勉、吉村友希、Qiang Ge、Robert pawlosky、R. Max Wynn、山本和宏、平 野剛、Richard L. Veech、Kosaku Uyeda、平井みどり
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 国立京都国際会館（京都府・京都市）
  • Year and Date: 2014-10-15 – 2014-10-18
• [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] 神戸大学大学院医学研究科 薬物動態学・薬剤学分野ホームページ
  • 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/kobepharm.html