Mechanism of lifestyle diseases with particular attentions to the brain-lipid sensing

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K01814
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Applied health science
• Research Institution: Kanazawa University
• Principal Investigator: Yamashina Tetsumori 金沢大学, 医学系, 協力研究員 (60135077)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: サラダ油 / ヒドロキシノネナール / 脂肪毒性 / 生活習慣病 / GPR40 / Hasp70.1 / リソソーム / 細胞死

Outline of Final Research Achievements

Deep-fried foods cooked by ω-6 oil contain or intrinsically generate hydroxynonenal by peroxidation. Hydroxynonenal promotes carbonylation of Hsp70.1 proteins, with the resultant impaired ability of cells to recycle damaged proteins and stabilize the lysosomal membrane. As the ‘calpain-cathepsin hypothesis’ has been documented as a cause of ischemic and Alzheimer neuronal death, its relevance to cell death of the hypothalamus, liver, and pancreas, being related to the appetite/energy control, was studied here. The hypothalamus senses informations from both adipocyte-derived leptin and circulating free fatty acids. Since circulating fatty acids and hydroxynonenal are increased in obese subjects, the resultant overactivation of GPR40 may cause disruption of Ca2+ homeostasis and activated calpain-mediated cleavage of the carboxylated Hsp70.1 which lead to the lysosomal permeabilization/rupture to cause diverse cell death.

Free Research Field

健康科学

Academic Significance and Societal Importance of the Research Achievements

本研究では、世界的に様々な疾患モデルで追試されて来た研究代表者提唱の「カルパイン-カテプシン仮説」に基づき、ω－６系の食用油を多量に摂るヒトに好発するアルツハイマー病や非アルコール性脂肪性肝炎（NASH）及び２型糖尿病などの病因を、ヒドロキシノネナール（HNE）などの過酸化脂質に着目して究明し得た。すなわち、『酸化損傷（カルボニル化）とカルパイン切断がもたらすHsp70.1の異常に起因するリソソーム膜の破綻』をサルモデルで検証し、生活習慣病の根本原因を見直すことができた。
本研究は、生活習慣病の発症におけるω-６系サラダ油のリスクに関して、研究代表者独自の作業仮説に基づき世界初の成果をあげた。