Elucidation of intracellular import and metabolic circuits involving CD147/Basigin and development of novel therapeutics through regulation of sugar chain modification

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K09695
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Kidney internal medicine
• Research Institution: Nagoya University
• Principal Investigator: Kosugi Tomoki 名古屋大学, 医学系研究科, 講師 (90584681)
• Co-Investigator(Kenkyū-buntansha): 丸山 彰一 名古屋大学, 医学系研究科, 教授 (10362253) ; 門松 健治 名古屋大学, 医学系研究科, 教授 (80204519)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: CD147/Basigin / 乳酸 / ピルビン酸 / 高脂肪食 / エネルギー恒常性 / 脂肪性肝疾患 / 慢性腎臓病

Outline of Final Research Achievements

In the present study, we aimed to elucidate the underlying mechanisms of chronic kidney disease (CKD) and hepatic steatosis caused by nutritional overburden more in details. Therefore, we investigated the role of CD147/Basigin (BSG) to maintain intracellular energy homeostasis, using high fat diet (HFD)-induced wild-type and BSG gene-deficient (BSGKO) mice. In the kidneys of BSGKO mice, vacuolar degeneration of tubular epithelial cells and accumulation of lipofuscin-like substances were remarkably suppressed. These findings might be due to the phenomena that transport of the substrates such as pyruvate and lactate in the cells was suppressed by BSG deficits subsequently leading to the the reduction of TCA cycle intermediates and enhanced ketogenesis through activation of free fatty acid beta oxidation. In the setting, augmented BSG protein might be due to the promotion of autophagy, but not translocation to nuclei.

Free Research Field

Nephrology

Academic Significance and Societal Importance of the Research Achievements

近年、乳酸やピルビン酸の代謝やケトン体合成経路に関する研究は脳神経細胞や心遅筋線維のエネルギー源としての研究から内因性代謝物の細胞内蓄積・臓器障害に至るまで多岐におよぶ。BSGもまた、乳酸やピルビン酸、ケトン体のミトコンドリア取り込みに関与しエネルギー恒常性の維持に寄与するLactate Shuttle理論(未検証)が提唱されている。そのため、糖尿病による腎臓・肝臓障害に対して、細胞内のエネルギー恒常性の変化を俯瞰することは新たな治療戦略の構築となり、BSGを治療標的とする事はエネルギー恒常性を制御し、現在医療経済上負担となっている多彩な糖尿病関連疾患の抑止につながる。