01Research overview

Development of new strategies for the treatment of lifestyle-related disease by qualitative control of fatty acids

The prevalence of obesity and metabolic disease has grown to epidemic proportions around the world, including in Japan. As such, there is an urgent need to better understand the molecular basis of energy metabolism and to provide new development leads for effective therapeutic approaches which prevent lifestyle-related diseases.

We are working to understand the molecular mechanisms of nutrient signals, and which of those lead to fatty acid synthesis. In this process, we have identified and characterized a novel mammalian fatty acid elongase, Elovl6. This catalyzes the elongation of saturated and monounsaturated fatty acids with 12, 14, and 16 carbons.

We have shown that mice with targeted disruption of Elovl6 are resistant to obesity-induced insulin resistance, impaired insulin secretion and obesity-related disorders, despite developing obesity. Results suggest that inhibition of this elongase could be a new therapeutic approach for the treatment of diabetes, nonalcoholic fatty liver disease (NAFLD), cardiovascular disease and other metabolic diseases, even with concurrent obesity.

The long-term goal for our laboratory is to fully understand the role of Elovl6 in health and disease, and to elucidate the molecular mechanisms by which Elovl6 regulates energy metabolism, cellular function and disease formation through modulating the quality of fatty acids. We are also advancing our investigation findings to develop new therapeutic approaches for treatment of lipid-related diseases. Ultimately, we aim to provide approaches to help solve disease conditions such as metabolic syndrome, neurodegenerative disease and cancer based on control of fatty acid composition.

01研究概要

脂肪酸の質的制御による新しい生活習慣病治療法の開発

近年の肥満ならびに生活習慣病患者の増加により、これら疾患の予防および治療に対しての有効な方法が早急に求められています。我々は、炭素数12-16の飽和・一価不飽和脂肪酸を基質とする脂肪酸伸長酵素Elongation of very long chain fatty acids member 6（Elovl6）をクローニングし、Elovl6欠損マウスの各臓器や血液では脂肪酸組成が鎖長や不飽和度に応じて著しく変化するとともに、肥満にともなうインスリン抵抗性、2型糖尿病、非アルコール性脂肪性肝炎（NASH）、動脈硬化など様々な生活習慣病の発症・進展が抑制されることを明らかにしました。すなわち、臓器や細胞に蓄積する脂質の「量」のみならず、脂肪酸の組成といった脂質の｢質｣もエネルギー代謝の重要な決定因子であり、Elovl6の阻害は肥満が持続した状態においてもインスリン抵抗性、糖尿病、心血管リスクを改善する新たな治療法となる可能性があります。

そこで、本研究では、Elovl6を中心に脂肪酸の質から生活習慣病、神経変性疾患、がんなどの病態を解明し、脂肪酸組成のコントロールを基盤とした代謝関連疾患の新規予防法・治療法の開発を目指します。