Therapeutic strategy for lipotoxicity of pancreatic beta-cells by activation of HDL metabolism

• Project/Area Number: 15K09415
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Kagawa University
• Principal Investigator: MURAO Koji 香川大学, 医学部, 教授 (20291982)
• Co-Investigator(Kenkyū-buntansha): 大森 浩二 香川大学, 医学部, 准教授 (00263913) ; 井町 仁美 香川大学, 医学部, 准教授 (80380187)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2016: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 糖尿病 / 代謝学 / HDL代謝 / 膵β細胞 / 脂肪毒性 / トランスレーショナルリサーチ / 細胞内情報伝達系 / インスリン分泌 / ABCA1 / HDL / 膵β脂肪 / 転写調節 / 転写因子PREB / PREB / Akt / PI3K / insulin / IGF-I

Outline of Final Research Achievements

Recently, abnormalities in cholesterol metabolism have emerged as a potential contributor to beta-cell dysfunction. ATP-binding cassette transporter A1 (ABCA1), a cytoplasmic membrane protein, is a pivotal regulator of lipid efflux from cells to apolipoproteins and plays an important role in reverse cholesterol transport. Pancreatic islets isolated from ABCA1-deficient mice demonstrated altered cholesterol homeostasis and impaired insulin secretion in vitro. We have revealed the link between ABCA1 signal transduction pathway and transcriptional factor that regulated ABCA1 gene expression. Pancreatic islets isolated from these mice demonstrated altered cholesterol homeostasis and impaired insulin secretion in vitro. These results establish a new role for the ABCA1 gene in beta cell cholesterol homeostasis and insulin secretion, indicating that cholesterol accumulation may contribute to beta cell dysfunction in type 2 diabetes, so called “pancreatic lipotoxicity”.

Research Products

• [Journal Article] Thyroid stimulating hormone stimulates the expression of glucose transporter 2 via its receptor in pancreatic β cell line, INS-1 cells. (2018)
  • Author(s): Lyu J, Imachi H, Yoshimoto T, Fukunaga K, Sato S, Ibata T, Kobayashi T, Dong T, Yonezaki K, Yamaji N, Kikuchi F, Iwama H, Ishikawa R, Haba R, Sugiyama Y, Zhang H, Murao K.
  • Journal Title: Sci Rep. Volume: 8 Issue: 1 Pages: 1986-1995
  • DOI: 10.1038/s41598-018-20449-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cardioprotective Effects of Serca2a Overexpression Against Ischemiareperfusion- induced Injuries in Rats (2017)
  • Author(s): Jiang Yan、Tian Li-Li、Wang Lin-Hui、Zhao Xiao-Dong、Chen Jing-Wei、Murao Koji、Zhu Wei、Dong Liang、Wang Guo-Qing、Sun Wan-Ping、Zhang Guo-Xing
  • Journal Title: Curr Gene Ther Volume: 17 Issue: 3 Pages: 248-258
  • DOI: 10.2174/1566523217666171110175251
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Effects of sodium-glucose cotransporter 2 inhibitors on urinary excretion of intact and total angiotensinogen in patients with type 2 diabetes (2017)
  • Author(s): Yoshimoto Takuo、Furuki Takayuki、Kobori Hiroyuki、Miyakawa Masaaki、Imachi Hitomi、Murao Koji、Nishiyama Akira
  • Journal Title: J Investig Med Volume: 65 Issue: 7 Pages: 1057-1061
  • DOI: 10.1136/jim-2017-000445
  • Peer Reviewed
• [Journal Article] Prolactin regulatory element-binding protein is involved in suppression of the adiponectin gene in vivo (2017)
  • Author(s): Zhang XZ, Imachi H, Lyu JY, Fukunaga K, Sato S, Ibata T, Kobayashi T, Yoshimoto T, Kikuchi F, Dong T, Murao K
  • Journal Title: J Endocrinol Invest Volume: 40 Issue: 4 Pages: 437-445
  • DOI: 10.1007/s40618-016-0589-3
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Insulin-like Growth Factor 1 Regulates the Expression of ATP-Binding Cassette Transporter A1 in Pancreatic Beta Cells (2016)
  • Author(s): Lyu J, Imachi H, Iwama H, Zhang H, Murao K
  • Journal Title: Horm Metab Res Volume: 47 Issue: 05 Pages: 1-7
  • DOI: 10.1055/s-0035-1569272
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Immunoreactive insulin in diabetes mellitus patient sera detected by ultrasensitive ELISA with thio-NAD cycling (2015)
  • Author(s): Ito E, Kaneda M, Kodama H, Morikawa M, Tai M, Aoki K, Watabe S, Nakaishi K, Hashida S, Tada S, Kuroda N, Imachi H, Murao K, Yamashita M, Yoshimura T, Miura T
  • Journal Title: Biotechniques Volume: 59 Issue: 6 Pages: 361-367
  • DOI: 10.2144/000114355
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Roles of lipoprotein receptors in the entry of hepatitis C virus (2015)
  • Author(s): Lyu J, Imachi H, Fukunaga K, Yoshimoto T, Zhang H, Murao K
  • Journal Title: World J Hepatol Volume: 7 Issue: 24 Pages: 2535-2542
  • DOI: 10.4254/wjh.v7.i24.2535
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] 香川大学における生活習慣病への取り組み (2017)
  • Author(s): 村尾孝児、井町仁美
  • Organizer: 第13回合同地方会
  • Invited
• [Presentation] ICT、K-MIXを介した香川県での糖尿病地域医療連携 (2017)
  • Author(s): 村尾孝児、井町仁美
  • Organizer: 第51回糖尿病学の進歩
  • Invited
• [Presentation] 糖尿病の病態形成におけるHDL代謝の関与 (2016)
  • Author(s): 村尾孝児
  • Organizer: 第48回日本動脈硬化学会総会・学術集会
  • Place of Presentation: 東京
  • Year and Date: 2016-07-14
• [Presentation] 糖尿病におけるHDL代謝 (2015)
  • Author(s): 村尾孝児、井町仁美、吉本卓生、菊池史、永田宙生
  • Organizer: 第 58 回日本糖尿病学会年次学術集会
  • Place of Presentation: 下関
  • Year and Date: 2015-05-21
  • Invited
• [Presentation] 膵β細胞株 INS-1 における ABCA1 遺伝子発現に及ぼす AGEs の影響について (2015)
  • Author(s): 張暁舟、井町仁美、呂静雅、福長健作、小林俊博、井端智裕、永田宙生、菊池 史、吉本卓生、西内崇将、村尾孝児
  • Organizer: 第88回日本内分泌学会学術総会
  • Place of Presentation: 東京
  • Year and Date: 2015-04-23
• [Presentation] 肝細胞におけるABCA1遺伝子発現に及ぼすGLP-1の影響について (2015)
  • Author(s): 呂静雅、 井町仁美、張暁舟、福長健作、小林俊博、井端智裕、永田宙生、菊池史、吉本 卓生、西内崇将、村尾孝児
  • Organizer: 88 回日本内分泌学会学術総会
  • Place of Presentation: 東京
  • Year and Date: 2015-04-23