Therapeutic strategy for lipotoxicity of pancreatic beta-cells

• Project/Area Number: 24591352
• 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): IMACHI Hitomi 香川大学, 医学部, 准教授 (80380187) ; TOKUMITSU Hiroshi 岡山大学, 自然科学研究, 教授 (20237077) ; OHMORI Koji 香川大学, 医学部, 准教授 (00263913)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2014: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2013: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000); Fiscal Year 2012: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 糖尿病 / 代謝学 / HDL代謝 / 膵β細胞 / 脂肪毒性 / 糖毒性 / 細胞内情報伝達系 / インスリン分泌 / ABCA1 / GLP-1 / CaMKIV

Outline of Final Research Achievements

The reasons for beta-cell dysfunction in type 2 diabetes are incompletely understood. 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. A recent study reported that mice with specific inactivation of the Abca1 gene in their beta cells had markedly impaired glucose tolerance and defective insulin secretion, but normal insulin sensitivity. 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] Contribution of the renin-angiotensin system in chronic foot-shock induced hypertension in rats. (2015)
  • Author(s): Wang LH, Dong T, Liu BB, Zhao XD, Chen JW, Murao K, Zhu W, Zhang GX
  • Journal Title: Life Sci Volume: 121 Pages: 135-144
  • DOI: 10.1016/j.lfs.2014.12.004
  • Peer Reviewed / Open Access
• [Journal Article] Decreased expression of platelet human scavenger receptor class B type I in patients with type 2 diabetes mellitus. (2014)
  • Author(s): Imachi H, Fukata Y, Murao K
  • Journal Title: J Diabetes Investig Volume: 5 Issue: 3 Pages: 345-346
  • DOI: 10.1111/jdi.12158
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Mitochondrial KATP channel involvement in angiotensin II-induced autophagy in vascular smooth muscle cells (2014)
  • Author(s): Yu KY, Wang YP, Wang LH, Jian Y, Zhao XD, Chen JW, Murao K, Zhu W, Dong L, Wang GQ, Zhang GX
  • Journal Title: Basic Res Cardiol Volume: 109 Issue: 4 Pages: 416-416
  • DOI: 10.1007/s00395-014-0416-y
  • Peer Reviewed / Open Access
• [Journal Article] 17β-Estradiol regulates scavenger receptor class BI gene expression via protein kinase C in vascular endothelial cells (2014)
  • Author(s): Fukata Y, Yu X, Imachi H, Nishiuchi T, Lyu J, Seo K, Takeuchi A, Iwama H, Masugata H, Hoshikawa H, Hosomi N, Iwasaki Y, Murao K
  • Journal Title: Endocrine Volume: 46 Issue: 3 Pages: 644-650
  • DOI: 10.1007/s12020-013-0134-5
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 17β-Estradiol regulates scavenger receptor class BI gene expression via protein kinase C in vascular endothelial cells. (2014)
  • Author(s): Fukata Y, Yu X, Imachi H, Nishiuchi T, Lyu J, Seo K, Takeuchi A, Iwama H, Masugata H, Hoshikawa H, Hosomi N, Iwasaki Y, Murao K.
  • Journal Title: Endocrine Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Metformin Suppresses Expression of the Selenoprotein P gene via an AMPK-FoxO3a Pathway in H4IIEC3 Hepatocytes (2014)
  • Author(s): H Takayama, H Misu, H Iwama, K Chikamoto, Y Saito, K Murao, A Teraguchi, F Lan, A Kikuchi, R Saito, N Tajima, T Shirasaki, S Matsugo, KI Miyamoto, S Kaneko, T Takamura
  • Journal Title: J Biol Chem Volume: 289(1) Issue: 1 Pages: 335-45
  • DOI: 10.1074/jbc.m113.479386
  • Peer Reviewed
• [Journal Article] Human microRNAs originated from two periods at accelerated rates in mammalian evolution (2013)
  • Author(s): Iwama H, Kato K, Imachi H, Murao K, Masaki T
  • Journal Title: Mol Biol Evol Volume: 30(3) Issue: 3 Pages: 613-26
  • DOI: 10.1093/molbev/mss262
  • Peer Reviewed
• [Journal Article] Liver X receptorαis involved in the transcriptional regulation of the 6-phosphofructo-2- kinase/fructose-2,6-bisphosphatase gene (2012)
  • Author(s): Zhao LF, Iwasaki Y, Nishiyama M, Taguchi T, Tsugita M, Okazaki M, Nakayama S, Kambayashi M, Fujimoto S, Hashimoto K, Murao K, Terada Y
  • Journal Title: Diabetes Volume: 61 Issue: 5 Pages: 1062-1071
  • DOI: 10.2337/db11-1255
  • Peer Reviewed
• [Presentation] 膵β細胞におけるABCA1発現に及ぼすIGF-Iの影響について (2014)
  • Author(s): 村尾孝児、呂 静雅、井町仁美、深田陽子、西内崇将、吉本卓生、福長健作、岩間久和、岩崎泰正
  • Organizer: 第57回日本糖尿病学会年次学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2014-05-22 – 2014-05-24
• [Presentation] GLP-1 analogのよる肝ABCA1発現誘導に転写因子PREBが関与する (2014)
  • Author(s): 井町仁美、呂 静雅、深田陽子、西内崇将、菊池 史、吉本卓生、福長健作、篁 俊成、村尾孝児
  • Organizer: 第57回日本糖尿病学会年次学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2014-05-22 – 2014-05-24
• [Presentation] 膵β細胞におけるABCA1発現に及ぼすIGF-Iの影響について (2014)
  • Author(s): 村尾孝児、井町仁美、呂静雅、深田陽子、西内崇将
  • Organizer: 第５７回日本糖尿病学会総会
  • Place of Presentation: 大阪府
• [Presentation] 糖毒性によるインスリン分泌抑制機序の関わるプロテインキナーゼの網羅的解析 (2012)
  • Author(s): 村尾孝児、井町仁美、村岡都美江、大山知代、菊池 史、岩崎泰正
  • Organizer: 第５５回日本糖尿病学会総会
  • Place of Presentation: 横浜
• [Book] SR-BI (2015)
  • Author(s): 村尾孝児、井町仁美、深田陽子、西内崇将
  • Total Pages: 477
  • Publisher: 株式会社エル・アイ・シー