Mechanism of insulin resistance by fatty acids via selenoprotein P

• Project/Area Number: 16K09739
• 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: TAKESHITA YUMIE 金沢大学, 医学系, 准教授 (40507042)
• 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: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2016: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: ヘパトカイン / インスリン抵抗性 / 脂肪酸 / イコサペンタエン酸 / EPA

Outline of Final Research Achievements

Selenoprotein P (encoded by SELENOP in humans, Selenop in rat), a liver-derived secretory protein, induces resistance to insulin and VEGF in type 2 diabetes. The present findings demonstrate that EPA suppresses SELENOP expression by inactivating SREBP-1c in H4IIEC3 hepatocytes. Treatment with EPA caused concentration- and time-dependent reduction in SELENOP promoter activity. EPA activated AMPK; however, the inhibitory effect of EPA on SELENOP promoter activity was not canceled with an AMPK inhibitor compound C and dominant-negative AMPK transfection. Deletion mutant promoter assays and computational analysis of transcription factor-binding sites conserved among the species resulted in identification of a SRE-like site in the SELENOP promoter. A ChIP assay revealed that EPA decreases binding of SREBP-1c to the SELENOP promoter. Knockdown of Srebf1 resulted in a significant down-regulation of Selenop expression. SREBP-1c overexpression inhibited the suppressive effect of EPA.

Academic Significance and Societal Importance of the Research Achievements

我々はこれまでに、セレノプロテインP (SeP) がインスリン抵抗性を誘導する”ヘパトカイン”であることを報告してきた。H4IIEC肝細胞において、パルミチン酸 (PA)はSREBP-1c経路非依存的にSeP発現を誘導すること、エイコサペンタエン酸 (EPA)はSREBP-1cの核移行を抑制し、不活化を介して肝臓でのSeP発現を抑制することを示唆した。よって、EPAによるSeP発現抑制は全身インスリン抵抗性を改善する可能性がある。今後、マウスおよび臨床サンプルを利用したさらなる研究が、EPAの全身のインスリン抵抗性改善薬としての新たな臨床的有用性を明らかにすることが期待される。

Research Products

• [Journal Article] Study Protocol for Pleiotropic Effects and Safety of Sodium-Glucose Cotransporter 2 Inhibitor Versus Sulfonylurea in Patients with Type 2 Diabetes and Nonalcoholic Fatty Liver Disease. (2020)
  • Author(s): Takeshita Y, Kanamori T, Tanaka T, Kaikoi Y, Kita Y, Takata N, Iida N, Arai K, Yamashita T, Harada K, Gabata T, Nakamura H, Kaneko S, Takamura T.
  • Journal Title: Diabetes Ther. Volume: 11 Issue: 2 Pages: 549-560
  • DOI: 10.1007/s13300-020-00762-9
  • Peer Reviewed / Open Access
• [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] A novel PHEX mutation associated with vitamin D-resistant rickets (2019)
  • Author(s): Sako Saori、Niida Yo、Shima Kosuke Robert、Takeshita Yumie、Ishii Kiyo-aki、Takamura Toshinari
  • Journal Title: Human Genome Variation Volume: 6 Issue: 1 Pages: 1-3
  • DOI: 10.1038/s41439-019-0040-3
  • Peer Reviewed / Open Access
• [Journal Article] Consuming Carbohydrates after Meat or Vegetables Lowers Postprandial Excursions of Glucose and Insulin in Nondiabetic Subjects (2018)
  • Author(s): Nishino K, Sakurai M, Takeshita Y,Takamura T.
  • Journal Title: Journal of Nutritional Science and Vitaminology Volume: 64 Issue: 5 Pages: 316-320
  • DOI: 10.3177/jnsv.64.316
  • NAID: 130007501949
  • ISSN: 0301-4800, 1881-7742
  • Year and Date: 2018-10-31
  • Open Access
• [Journal Article] Effects of metformin and alogliptin on body composition in people with type 2 diabetes. (2018)
  • Author(s): Takeshita Y, Kita Y, Kato KI, Kanamori T, Misu H, Kaneko, Takamura T.
  • Journal Title: J Diabetes Investig Volume: Aug Issue: 3 Pages: 29-29
  • DOI: 10.1111/jdi.12920
  • Peer Reviewed / Open Access
• [Journal Article] Mealtime dosing of a rapid-acting insulin analog reduces glucose variability and suppresses daytime cardiac sympathetic activity: a randomized controlled study in hospitalized patients with type 2 diabetes. (2018)
  • Author(s): Kanamori T, Takeshita Y, Isobe Y, Kato KI, Misu H, Kaneko, Takamura T.
  • Journal Title: BMJ Open Diabetes Res Care Volume: 6 Issue: 1 Pages: e000588-e000588
  • DOI: 10.1136/bmjdrc-2018-000588
  • 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] Vanishing of ruptured adrenal mass with takotsubo cardiomyopathy. (2018)
  • Author(s): Takeshita Y, Teramura C, Takamura T.
  • Journal Title: Endocr J Volume: 65 Pages: 1155-1159
  • NAID: 130007553238
  • 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] 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] Weight-adjusted lean body mass and calf circumference are protective against obesity-associated insulin resistance and metabolic abnormalities. (2017)
  • Author(s): Takamura T, Kita Y, Nakagen M, Sakurai M, Isobe Y, Takeshita Y, Kawai K, Urabe T, Kaneko S.
  • Journal Title: Heliyon. Volume: 3 Issue: 7 Pages: e00347-e00347
  • DOI: 10.1016/j.heliyon.2017.e00347
  • Peer Reviewed / Open Access
• [Journal Article] Rapid response of the steatosis-sensing hepatokine LECT2 during diet-induced weight cycling in mice. (2016)
  • Author(s): Chikamoto K, Misu H, Takayama H, Kikuchi A, Ishii KA, Lan F, Takata N, Tajima-Shirasaki N, Takeshita Y, Tsugane H, Kaneko S, Matsugo S, Takamura T.
  • Journal Title: Biochem Biophys Res Commun. Volume: 478 Pages: 1310-1316
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Altered gene expression in T-cell receptor signalling in peripheral blood leucocytes in acute coronary syndrome predicts secondary coronary events. (2016)
  • Author(s): Takashima S, Usui S, Kurokawa K, Kitano T, Kato T, Murai H, Furusho H, Oda H, Maruyama M, Nagata Y, Usuda K, Kubota K, Takeshita Y, Sakai Y, Honda M, Kaneko S, Takamura M.
  • Journal Title: Open Heart. Volume: 3
  • NAID: 120005830627
  • Peer Reviewed / Open Access
• [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): Isobe Y, Sakurai M, Kita Y, Takeshita Y, Misu H, Kaneko S, Takamura T.
  • Journal Title: J Diabetes Investig. Volume: 7 Pages: 352-358
  • NAID: 120005682647
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Pleiotropic effects of sitagliptin versus voglibose in patients with type 2 diabetes inadequately controlled via diet and/or a single oral antihyperglycemic agent: a multicenter, randomized trial. (2016)
  • Author(s): Matsushima Y, Takeshita Y, Kita Y, Otoda T, Kato K, Toyama-Wakakuri H, Akahori H, Shimizu A, Hamaguchi E, Nishimura Y, Kanamori T, Kaneko S, Takamura T.
  • Journal Title: BMJ Open Diabetes Res Care. Volume: 4
  • Peer Reviewed / Open Access
• [Presentation] Pleiotropic effects of metformin or alogliptin in Japanese patients with type 2 diabetes (2019)
  • Author(s): Yumie Takeshita、Yuki Kita、Toshinari Takamura
  • Organizer: IDF Congress 2019
  • Int'l Joint Research
• [Presentation] 「GLP-1 First」療法vs.「Insulin-GLP-1 Relay」療法のランダム化並行群間比較試験 (2019)
  • Author(s): 竹下有美枝，喜多 裕樹，田中 健雄，金森 岳広，御簾博文， 篁 俊成
  • Organizer: 第６２回日本糖尿病学会年次学術集会
• [Presentation] トホグリフロジン12ヶ月の連続肝生検アウトカム (2019)
  • Author(s): 竹下 有美枝、喜多 裕樹、田中 健雄、金森 岳広、御簾 博文、篁 俊成
  • Organizer: 第９２回日本内分泌学会学術総会
• [Presentation] 前向き薬剤介入試験における血管内皮機能と臨床検査デー タの関連 (2019)
  • Author(s): 中田 晶子 ，竹下有美枝 ，高道小百合，中出 祐介，大江 宏康， 酒井 佳夫，篁 俊成，和田 隆志
  • Organizer: 第６２回日本糖尿病学会年次学術集会
• [Presentation] 非アルコール性脂肪性肝疾患（NAFLD）の連続肝生検realworld data：高血糖の肝線維化への寄与 (2019)
  • Author(s): 迫 佐央理 ，竹下有美枝 ，安藤 仁 ，御簾 博文 ，辻口 博聖 ， 中村 裕之 ，原田 憲一 ，金子 周一 ，篁 俊成
  • Organizer: 第６２回日本糖尿病学会年次学術集会
• [Presentation] EPA製剤が2型糖尿病患者の血中セレノプロテインP濃度と臓器特異的インスリン感受性に及ぼす効果 (2019)
  • Author(s): 寺村千里，竹下有美枝，高山浩昭 ，海古井由佳，田中健雄，金森岳広，篁俊成
  • Organizer: 第34回日本糖尿病合併症学会
• [Presentation] インスリン抵抗性や運動抵抗性を惹起するセレノプロテインPに対するEPAの制御機構 (2019)
  • Author(s): 鴨下恭子，石井清明，田島奈津美，白崎尚芳，高山浩昭，竹下有美枝，金子周一，篁俊成
  • Organizer: 第34回日本糖尿病合併症学会
• [Presentation] 肝臓由来ホルモン selenoprotein P の脂肪酸による発現制御機構：培養肝細胞とヒトでの検討 (2019)
  • Author(s): 鴨下恭子，石井清明，寺村千里，高山浩昭，田中健雄，金森岳広，米田隆，竹下有美枝，篁俊成
  • Organizer: 第１９回日本内分泌学会北陸支部学術集会
• [Presentation] ２型糖尿病患者を対象とした「GLP-1 First」療法および「Insulin GLP-1 Relaｙ」療法のランダム化並行郡間比較試験(中間解析) (2018)
  • Author(s): 竹下有美枝、喜多祐樹、田中健雄、井川寛章、中川浩実、島孝佑、金森岳広、御簾博文、篁 俊成
  • Organizer: 第61回日本糖尿病学会年次学術集会
• [Presentation] Effects of metformin and alogliptin on body composition in Japanese people with type 2 diabetes (2018)
  • Author(s): Yumie TAKESHITA, Yuki KITA、Toshinari TAKAMURA
  • Organizer: The 3rd World Congress on Clinical Trials in Diabetes
  • Int'l Joint Research
• [Presentation] SGLT2阻害薬1年間の連続肝生検アウトカム (2018)
  • Author(s): 竹下有美枝、喜多裕樹、中田竜介、田中健雄、金森岳広、御簾博文、篁 俊成
  • Organizer: 第33回日本糖尿病合併症学会
• [Presentation] The effect of ursodeoxycholic acid added to dipeptidyl peptidase-4 inhibitor on GLP-1 secretion and glucose tolerance in subjects with type 2 diabetes. (2017)
  • Author(s): Shima K R,Takeshita Y, Misu H, Ota T,Takamura T
  • Organizer: American Diabetes Association’s 77th Scientific Sessions ,ADA
  • Int'l Joint Research
• [Book] 糖尿病 最新の治療 2019-2021 (2019)
  • Author(s): 竹下有美枝 篁俊成
  • Total Pages: 337
  • Publisher: 南江堂
• [Book] ひと味違うSGLT2阻害薬の使い方 (2019)
  • Author(s): 竹下有美枝 篁俊成
  • Total Pages: 190
  • Publisher: 中外医学社
• [Book] 二次性糖尿病 2.肝疾患を合併した糖尿病 (2019)
  • Author(s): 竹下有美枝 篁俊成
  • Total Pages: 3
  • Publisher: 最新の治療2019-2021 南江堂
• [Book] 肥満に伴う臓器障害 肥満に伴う臓器障害の成因と病態 肥満と肝障害 (2017)
  • Author(s): 竹下有美枝 篁俊成
  • Total Pages: 4
  • Publisher: ホルモンと臨床 医学の世界社
• [Book] Global hepatitis report, 2017 (2017)
  • Author(s): WHO staff members
  • Total Pages: 87
  • Publisher: WHO
• [Book] 糖尿病治療薬 クリニカルクエスチョン120 (2016)
  • Author(s): 竹下有美枝 篁俊成
  • Total Pages: 264
  • Publisher: 診断と治療社