Significance of glycosylphosphatidylinositol-specific phospholipase D in metabolic disorders

• Project/Area Number: 18K16229
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54040:Metabolism and endocrinology-related
• Research Institution: Osaka University
• Principal Investigator: Fujishima Yuya 大阪大学, 医学系研究科, 助教 (10779789)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: GPI-PLD / 脂肪肝 / 肥満症 / 2型糖尿病 / メタボリックシンドローム / XOR / 動脈硬化症 / 糖尿病 / 肥満 / ２型糖尿病 / インスリン抵抗性 / ジアシルグリセロール

Outline of Final Research Achievements

GPI-PLD is an enzyme which specifically cleaves GPI anchors. However, the biological roles of GPI-PLD have not been elucidated. GPI-PLD mRNA was most highly expressed in liver, and hepatic mRNA level and circulating concentration of GPI-PLD were significantly augmented in diabetic conditions. Mice lacking GPI-PLD (GP-KO mice) exhibited the amelioration of glucose intolerance and hepatic steatosis in diet-induced obesity model. Furthermore, diacylglycerol (DAG) content was significantly decreased in livers of GP-KO mice. In vitro experiments using rat primary hepatocytes showed the GPI-PLD-dependent regulation of intracellular DAG content. Finally, serum GPI-PLD levels were strongly and independently associated with serum ALT and triglyceride (TG) levels in the male subjects with metabolic syndrome.
In conclusion, up-regulation of hepatic GPI-PLD leads to DAG accumulation in liver, which may play a causal role in impaired hepatic insulin signaling and progression of fatty liver.

Academic Significance and Societal Importance of the Research Achievements

肝GPI-PLDの生理・病態的な役割はこれまで未知であったが脂肪肝や糖尿病の発症・進展に関わる可能性ならびに、その想定されるメカニズムの一端を、本研究により明らかにすることができた。
GPI-PLDは酵素であることから、その阻害薬による糖尿病や脂肪肝の治療展開も期待され、新たな治療薬の開発につながる可能性が導かれた。

Research Products

• [Journal Article] Increased vascular permeability and severe renal tubular damage after ischemia-reperfusion injury in mice lacking adiponectin or T-cadherin. (2021)
  • Author(s): Tsugawa-Shimizu Y, Fujishima Y, Kita S, Minami S, Sakaue TA, Nakamura Y, Okita T, Kawachi Y, Fukuda S, Namba-Hamano T, Takabatake Y, Isaka Y, Nishizawa H, Ranscht B, Maeda N, Shimomura I.
  • Journal Title: Am J Physiol Endocrinol Metab. Volume: 320 Issue: 2 Pages: E179-E190
  • DOI: 10.1152/ajpendo.00393.2020
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Plasma xanthine oxidoreductase activity in Japanese patients with type 2 diabetes across hospitalized treatment. (2021)
  • Author(s): Kawachi Y, Fujishima Y, Nishizawa H, Nagao H, Nakamura T, Akari S, Murase T, Taya N, Omori K, Miyake A, Fukuda S, Takahara M, Kita S, Katakami N, Maeda N, Shimomura I.
  • Journal Title: J Diabetes Investig. Volume: - Issue: 8 Pages: 1512-1520
  • DOI: 10.1111/jdi.13467
  • NAID: 120006953385
  • Peer Reviewed / Open Access
• [Journal Article] Adiponectin Stimulates Exosome Release to Enhance Mesenchymal Stem-Cell-Driven Therapy of Heart Failure in Mice. (2020)
  • Author(s): Nakamura Y, Kita S, Tanaka Y, Fukuda S, Obata Y, Okita T, Nishida H, Takahashi Y, Kawachi Y, Tsugawa-Shimizu Y, Fujishima Y, Nishizawa H, Takakura Y, Miyagawa S, Sawa Y, Maeda N, Shimomura I.
  • Journal Title: Mol Ther. Volume: 28 Issue: 10 Pages: 2203-2219
  • DOI: 10.1016/j.ymthe.2020.06.026
  • Peer Reviewed / Open Access
• [Journal Article] A disintegrin and metalloproteinase 12 prevents heart failure by regulating cardiac hypertrophy and fibrosis (2020)
  • Author(s): Nakamura Yuto、Kita Shunbun、Tanaka Yoshimitsu、Fukuda Shiro、Obata Yoshinari、Okita Tomonori、Kawachi Yusuke、Tsugawa-Shimizu Yuri、Fujishima Yuya、Nishizawa Hitoshi、Miyagawa Shigeru、Sawa Yoshiki、Sehara-Fujisawa Atsuko、Maeda Norikazu、Shimomura Iichiro
  • Journal Title: American Journal of Physiology-Heart and Circulatory Physiology Volume: 318 Issue: 2 Pages: H238-H251
  • DOI: 10.1152/ajpheart.00496.2019
  • Peer Reviewed / Open Access
• [Journal Article] Impact of glycosylphosphatidylinositol-specific phospholipase D on hepatic diacylglycerol accumulation, steatosis, and insulin resistance in diet-induced obesity (2019)
  • Author(s): Masuda S, Fujishima Y, Maeda N, Tsugawa-Shimizu Y, Nakamura Y, Tanaka Y, Obata Y, Fukuda S, Nagao H, Kita S, Nishizawa H, Shimomura I
  • Journal Title: American Journal of Physiology-Endocrinology and Metabolism Volume: 316 Issue: 2 Pages: E239-E250
  • DOI: 10.1152/ajpendo.00319.2018
  • Peer Reviewed / Open Access
• [Presentation] 2型糖尿病・高度肥満症の治療による血漿XORの変化 (2019)
  • Author(s): 川知祐介、藤島裕也、村瀬貴代、中村敬志、宮崎安弘、西澤 均、喜多俊文、前田法一、土岐祐一郎、下村伊一郎
  • Organizer: 第92回日本内分泌学会学術総会
• [Presentation] 肥満脂肪組織におけるコリントランスポーター発現とコリン代謝動態の変化 (2019)
  • Author(s): 藤島裕也、川知祐介、長尾博文、西澤 均、中山康宗、馬場健史、永森收志、金井好克、喜多俊文、前田法一、福崎英一郎、下村伊一郎
  • Organizer: 第92回日本内分泌学会学術総会
• [Presentation] アディポネクチンの組織集積のメカニズムと，その抗糖尿病作用および臓器保護作用の解明 (2019)
  • Author(s): 藤島裕也、小幡佳也、福田士郎、喜多俊文、西澤 均、前田法一、下村伊一郎
  • Organizer: 第62回日本糖尿病学会年次学術集会
• [Presentation] 腎臓におけるAdiponectin・T-cadherinの局在と機能解析 (2019)
  • Author(s): 清水有理、藤島裕也、沖田朋憲、川知祐介、中村勇斗、田中紀實、増田重樹、小幡佳也、福田士郎、喜多俊文、西澤 均、前田法一、下村伊一郎
  • Organizer: 第62回日本糖尿病学会年次学術集会
• [Presentation] GPIアンカー特異的切断酵素；GPI-PLDは、肝ジアシルグリセロール蓄積と耐糖能異常に関与する (2018)
  • Author(s): 藤島裕也、増田重樹、喜多俊文、西澤 均、前田法一、下村伊一郎
  • Organizer: 第91回日本内分泌学会学術総会
• [Presentation] 肝臓におけるGPIアンカー切断酵素GPI-PLDの機能解析 (2018)
  • Author(s): 増田重樹、藤島裕也、喜多俊文、西澤 均、前田法一、下村伊一郎
  • Organizer: 第61回日本糖尿病学会年次学術集会
• [Presentation] 肥満脂肪組織におけるコリン代謝の変化 (2018)
  • Author(s): 川知祐介、長尾博文、藤島裕也、西澤 均、中山康宗、馬場健史、永森收志、金井好克、喜多俊文、福田士郎、前田法一、福崎英一郎、下村伊一郎
  • Organizer: 第39回日本肥満学会
• [Presentation] 腎臓におけるAdiponectinの局在と機能解析 (2018)
  • Author(s): 清水有理、藤島裕也、中村勇斗、小幡佳也、増田重樹、田中紀實、長尾博文、福田士郎、喜多俊文、西澤 均、前田法一、下村伊一郎
  • Organizer: 第39回日本肥満学会