Identification of a novel transcription factor that regulates diabetes-related hepatokine.

• Project/Area Number: 16K09740
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Kanazawa University
• Principal Investigator: Misu Hirofumi 金沢大学, 医学系, 准教授 (80447680)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 2型糖尿病 / ヘパトカイン / インスリン抵抗性 / 転写因子 / 糖代謝異常

Outline of Final Research Achievements

We reported that liver-derived secretory proteins SeP and LECT2 are proteins that induce insulin resistance and cause hyperglycemia. In this study, we establish a research base for developing a treatment for obesity type 2 diabetes. From the gene expression data in the liver of patients with type 2 diabetes, we were able to identify the transcription factor X that positively correlated with SeP and LECT2. Therefore, the liver-specific transcription factor X-deficient mouse was created. In these mice, the expression levels of transcription factor X and the expression levels of SeP and Lect2 were also decreased in the liver. Also, a decrease in gluconeogenic gene expression and a decrease in fasting blood glucose could be confirmed.

Academic Significance and Societal Importance of the Research Achievements

肝臓は膨大な種類の分泌タンパクの産生源であり、血液凝固因子やアルブミンの産生を介して血液凝固状態の調整や血漿浸透圧の維持などの機能を発揮している。しかしながら肝臓はあまりに膨大な種類の分泌タンパクを産生していることから、これらの機能解析はこれまで十分に行われてこなかった。そこで、本研究では肝臓が未知の分泌タンパクを産生することで2型糖尿病における全身の病態形成に寄与していることを示すことができた。また、これらを制御する因子も発見できたことで、新たな肥満２型糖尿病に対する治療を開発するための研究基盤を確立することができた。

Research Products

• [Journal Article] Circulating Concentrations of Insulin Resistance-Associated Hepatokines, Selenoprotein P and Leukocyte Cell-Derived Chemotaxin 2, during an Oral Glucose Tolerance Test in Humans (2019)
  • Author(s): Mohri K, Misu H, Takayama H, Ishii KA, Kikuchi A, Lan F, Enyama Y, Takeshita Y, Saito Y, Kaneko S,Takamura T.
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 42 Issue: 3 Pages: 373-378
  • DOI: 10.1248/bpb.b18-00549
  • NAID: 130007607371
  • ISSN: 0918-6158, 1347-5215
  • Year and Date: 2019-03-01
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Induction of Selenoprotein P mRNA during Hepatitis C Virus Infection Inhibits RIG-I-Mediated Antiviral Immunity. (2019)
  • Author(s): Murai K, Honda M, Shirasaki T, Shimakami T, Omura H, Misu H, Kita Y, Takeshita Y, Ishii KA, Takamura T, Urabe T, Shimizu R, Okada H, Yamashita T, Sakai Y, Kaneko S.
  • Journal Title: Cell Host Microbe Volume: 10;25(4) Issue: 4 Pages: 588-601
  • DOI: 10.1016/j.chom.2019.02.015
  • Peer Reviewed / Open Access
• [Journal Article] Identification of hepatokines involved in pathology of type 2 diabetes and obesity (2019)
  • Author(s): Misu Hirofumi
  • Journal Title: Endocrine Journal Volume: 66 Issue: 8 Pages: 659-662
  • DOI: 10.1507/endocrj.EJ19-0255
  • NAID: 130007696454
  • ISSN: 0918-8959, 1348-4540
• [Journal Article] Diagnostic and Prognostic Significance of Serum Levels of SeP (Selenoprotein P) in Patients With Pulmonary Hypertension (2019)
  • Author(s): Nobuhiro Kikuchi, Kimio Satoh, Taijyu Satoh, Nobuhiro Yaoita, Mohammad Abdul Hai Siddique, Junichi Omura, Ryo Kurosawa, Masamichi Nogi, Shinichiro Sunamura, Satoshi Miyata, Hirofumi Misu, Yoshiro Saito, Hiroaki Shimokawa
  • Journal Title: Arterioscler Thromb Vasc Biol. Volume: 39 Issue: 12 Pages: 2553-2562
  • DOI: 10.1161/atvbaha.119.313267
  • Peer Reviewed / Open Access
• [Journal Article] Serum selenoprotein P, but not selenium, predicts future hyperglycemia in a general Japanese population. (2018)
  • Author(s): Oo SM, Misu H, Saito Y, Tanaka M, Kato S, Kita Y, Takayama H, Takeshita Y, Kanamori T, Nagano T, Nakagen M, Urabe T, Matsuyama N, Kaneko S, Takamura T.
  • Journal Title: Sci Rep. Volume: 8 Issue: 1 Pages: 16727-16727
  • DOI: 10.1038/s41598-018-35067-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Inhibin betaE (INHBE) is a possible insulin resistance-associated hepatokine identified by comprehensive gene expression analysis in human liver biopsy samples (2018)
  • Author(s): M. Sugiyama, A. Kikuchi, H. Misu, H. Igawa, M. Ashihara, Y. Kushima, K. Honda, Y. Suzuki, Y. Kawabe, S. Kaneko and T. Takamura
  • Journal Title: PLoS One Volume: 13 Issue: 3 Pages: e0194798-e0194798
  • DOI: 10.1371/journal.pone.0194798
  • Peer Reviewed / Open Access
• [Journal Article] Ursodeoxycholic acid potentiates dipeptidyl peptidase-4 inhibitor sitagliptin by enhancing glucagon-like peptide-1 secretion in patients with type 2 diabetes and chronic liver disease: a pilot randomized controlled and add-on study (2018)
  • Author(s): K. R. Shima, T. Ota, K. I. Kato, Y. Takeshita, H. Misu, S. Kaneko and T. Takamura
  • Journal Title: BMJ Open Diabetes Res Care Volume: 6 Issue: 1 Pages: e000469-e000469
  • DOI: 10.1136/bmjdrc-2017-000469
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Endogenous Selenoprotein P, a Liver-Derived Secretory Protein, Mediates Myocardial Ischemia/Reperfusion Injury in Mice. (2018)
  • Author(s): Chikata A, Kato T, Usuda K, Fujita S, Maruyama M, Nagata Y, Sakagami S, Kanamori N, Yaegashi T, Saeki T, Kusayama T, Usui S, Furusho H, Kaneko S, Takamura M.
  • Journal Title: Int J Mol Sci. Volume: 19 Issue: 3 Pages: 878-878
  • DOI: 10.3390/ijms19030878
  • Peer Reviewed / Open Access
• [Journal Article] Eicosapentaenoic acid down-regulates expression of the selenoprotein P gene by inhibiting SREBP-1c protein independently of the AMP-activated protein kinase pathway in H4IIEC3 hepatocytes. (2017)
  • Author(s): Tajima-Shirasaki N, Ishii KA, Takayama H, Shirasaki T, Iwama H, Chikamoto K, Saito Y, Iwasaki Y, Teraguchi A, Lan F, Kikuchi A, Takeshita Y, Murao K, Matsugo S, Kaneko S, Misu H, Takamura T.
  • Journal Title: J Biol Chem. Volume: 292 Issue: 26 Pages: 10791-10800
  • DOI: 10.1074/jbc.m116.747006
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The influence of adiposity and acute exercise on circulating hepatokines in normal-weight and overweight/obese men (2017)
  • Author(s): Sargeant Jack A.、Aithal Guruprasad P.、Takamura Toshinari、Misu Hirofumi、Takayama Hiroaki、Douglas Jessica A.、Turner Mark C.、Stensel David J.、Nimmo Myra A.、Webb David R.、Yates Thomas、King James A.
  • Journal Title: Appl Physiol Nutr Metab Volume: 3 Issue: 5 Pages: 1-9
  • DOI: 10.1139/apnm-2017-0639
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Selenoprotein P-neutralizing antibodies improve insulin secretion and glucose sensitivity in type 2 diabetes mouse models (2017)
  • Author(s): Mita Yuichiro、Nakayama Kaho、Inari Shogo、Nishito Yukina、Yoshioka Yuya、Sakai Naoko、Sotani Kanade、Nagamura Takahiro、Kuzuhara Yuki、Inagaki Kumi、Iwasaki Miki、Misu Hirofumi、Ikegawa Masaya、Takamura Toshinari、Noguchi Noriko、Saito Yoshiro
  • Journal Title: Nature Communications Volume: 8 Issue: 1 Pages: 1658-1658
  • DOI: 10.1038/s41467-017-01863-z
  • Peer Reviewed / Open Access
• [Journal Article] Deficiency of the hepatokine selenoprotein P increases responsiveness to exercise in mice through upregulation of reactive oxygen species and AMP-activated protein kinase in muscle. (2017)
  • Author(s): H Misu, H Takayama, Y Saito, Y Mita, A Kikuchi, K Ishii, K Chikamoto, T Kanamori, N Tajima, F Lan, Y Takeshita, M Honda, M Tanaka, S Kato, N Matsuyama, Y Yoshioka, Iwayama K, Tokuyama K, Akazawa N, Maeda S, Takekoshi K, Matsugo S, Noguchi N, S Kaneko, T Takamura.
  • Journal Title: Nature Med Volume: 23 Issue: 4 Pages: 508-516
  • DOI: 10.1038/nm.4295
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Rapid response of the steatosis-sensing hepatokine LECT2 during diet-induced weight cycling in mice. (2016)
  • Author(s): K Chikamoto, H Misu, H Takayama, A Kikuchi, KA Ishii, F Lan, N Takata, N Tajima-Shirasaki, Y Takeshita, H Tsugane, S Kaneko, S Matsugo, T Takamura.
  • Journal Title: Biochem Biophys Res Commun Volume: 478 Issue: 3 Pages: 1310-1316
  • DOI: 10.1016/j.bbrc.2016.08.117
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Development of a Sol Particle Homogeneous Immunoassay for Measuring Full-Length Selenoprotein P in Human Serum. (2016)
  • Author(s): M. Tanaka, Y. Saito, H. Misu, S. Kato, Y. Kita, Y. Takeshita, T. Kanamori, T. Nagano, M. Nakagen, T. Urabe, T. Takamura, S. Kaneko, K. Takahashi and N. Matsuyama.
  • Journal Title: J Clin Lab Anal Volume: 30 Issue: 2 Pages: 114-122
  • DOI: 10.1002/jcla.21824
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Fat-free mass and calf circumference as body composition indices to determine non-exercise activity thermogenesis in patients with diabetes (2016)
  • Author(s): Y. Isobe, M. Sakurai, Y. Kita, Y. Takeshita, H. Misu, S. Kaneko, T. Takamura
  • Journal Title: J Diabetes Investig Volume: 7 Issue: 3 Pages: 352-358
  • DOI: 10.1111/jdi.12421
  • NAID: 120005682647
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Diabetes-associated systemic pathology induced by hepatokines (2019)
  • Author(s): 御簾 博文，篁 俊成
  • Organizer: 第６２回日本糖尿病学会年次学術集会
  • Invited
• [Presentation] Contribution of the hepatokine selenoprotein P to the various pathologies of type 2 diabetes (2019)
  • Author(s): Hirofumi Misu
  • Organizer: The 9th Federation of Asian and Oceanian Physiological Societies Congress: FAOPS2019
  • Int'l Joint Research / Invited
• [Presentation] ヘパトカインセレノプロテインPと糖尿病全身病態との関連 (2019)
  • Author(s): 御簾博文
  • Organizer: 第33回日本糖尿病・肥満動物学会
  • Invited
• [Presentation] ヘパトカインセレノプロテインPの2型糖尿病病態に対する多面的作用 (2018)
  • Author(s): 御簾博文
  • Organizer: 日本薬学会第138年会
  • Invited
• [Presentation] ヘパトカインによる糖代謝維持機構とその破綻 (2018)
  • Author(s): 御簾博文
  • Organizer: 第32回日本糖尿病肥満動物学会
  • Invited
• [Presentation] ヘパトカインセレノプロテインPが惹起する運動療法抵抗性に関する解析 (2017)
  • Author(s): 高山浩昭、御簾博文、菊地晶裕、石井清朗、斎藤芳郎、金子周一、篁俊成
  • Organizer: 第31回日本糖尿病肥満動物学会
  • Place of Presentation: 横浜
  • Year and Date: 2017-02-10
• [Presentation] “サイレンシングヘパトカイン”セレノプロテインPの過剰による2型糖尿病関連病態の発症 (2017)
  • Author(s): 御簾博文
  • Organizer: 生命科学系学会合同年次大会ConBio2017
• [Presentation] ヘパトカインセレノプロテインPと筋受容体LRP1は活性酸素・AMPK経路の抑制によって運動抵抗性を誘導する (2017)
  • Author(s): 御簾博文, 高山浩昭, 金森岳広, 菊地晶裕, 石井清朗, 金子周一, 篁. 俊成
  • Organizer: 第60回日本糖尿病会学術総会
• [Presentation] ヘパトカインセレノプロテインPと骨格筋受容体LRP1による”運動抵抗性”の発症 (2017)
  • Author(s): 御簾博文
  • Organizer: 第3回日本筋学会
  • Invited
• [Presentation] ヘパトカインSePは筋受容体LRP1を介して運動抵抗性を惹起する (2017)
  • Author(s): 御簾博文,高山浩昭, 金子周一, 篁. 俊成
  • Organizer: 第90回日本内分泌学会
• [Presentation] ヘパトカインセレノプロテインPの肥満関連病態に対する多面的効果 (2016)
  • Author(s): 御簾博文、篁俊成
  • Organizer: 第37回日本肥満学会
  • Place of Presentation: 東京
  • Year and Date: 2016-10-07
  • Invited
• [Presentation] ヘパトカインによる全身の恒常性制御 (2016)
  • Author(s): 御簾博文、篁俊成、金子周一
  • Organizer: 第3回肝臓と糖尿病・代謝研究会
  • Place of Presentation: 金沢
  • Year and Date: 2016-07-16
  • Invited
• [Presentation] Regulation of glucose metabolism and angiogenesis by hepatokines (2016)
  • Author(s): Hirofumi Misu
  • Organizer: The 48th Annual Scientific Meeting of the Japan Atherosclerosis Society
  • Place of Presentation: 東京
  • Year and Date: 2016-07-14
  • Int'l Joint Research / Invited
• [Presentation] ヘパトカインセレノプロテインPの過剰産生は筋受容体LRP1を介して運動療法抵抗性の原因となる (2016)
  • Author(s): 御簾博文 篁俊成 金子周一
  • Organizer: 第102回日本消化器病学会総会
  • Place of Presentation: 東京
  • Year and Date: 2016-04-22
• [Book] 臓器連環による生体恒常性の破綻と疾患 (2019)
  • Author(s): 春日 雅人
  • Total Pages: 212
  • Publisher: 羊土社
  • ISBN: 9784758103787