Molecular mechanisms and therapeutic targets of atherogenic hypertriglyceridemia

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K09858
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Metabolomics
• Research Institution: The University of Tokyo
• Principal Investigator: Okazaki Hiroaki 東京大学, 医学部附属病院, 助教 (80610211)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 動脈硬化 / 脂質異常症 / 高トリグリセライド血症 / 治療法開発 / 分子機構 / 遺伝子-環境連関

Outline of Final Research Achievements

Recent genetic studies implicate a causative role of hypertriglyceridemia (HTG) in atherosclerotic diseases. However, effective therapeutic modalities are still lacking for HTG, and a better understanding of its molecular mechanisms is warranted. We focused on the APOA5 gene, which is one of the most dominant genes of atherogenic HTG. We established that apoA5 knockout mice can serve as an animal model of environment-induced HTG. Furthermore, we found that SREBP-1c, a transcriptional factor that regulates lipogenesis in the liver, plays an essential role in the environment (aging, high-carbohydrate diet, etc.)-induced HTG via the production of large-sized VLDL particles. These environmental factors activate the SREBP-1c-large VLDL pathway, and in the face of a genetic predisposition for delayed VLDL clearance (e.g., apoA5 deficiency) these large VLDLs accumulate in plasma, causing HTG. Further studies are underway to develop novel therapeutics to treat HTG and atherosclerosis.

Free Research Field

エネルギー代謝と動脈硬化

Academic Significance and Societal Importance of the Research Achievements

最近の遺伝疫学的研究などから、高中性脂肪（TG）血症は高LDL-コレステロール血症に次ぐ大きな動脈硬化リスクであることが示唆されているが、未だ有効な治療法に乏しい。高TG血症の発症・増悪の分子メカニズムや治療標的が同定されれば、動脈硬化症の新たな治療法開発に道を開く。本研究では、動脈硬化惹起性高TG血症のモデルマウスを世界に先駆けて確立した。さらにこの独自の動物モデルを用いて、環境要因が高TG血症を増悪させる分子メカニズムを解明した。これらの成果は、高TG血症と動脈硬化の新たな創薬の基盤となる。糖尿病を始め、高TG血症が動脈硬化リスクとなる多くの患者に役立つ新たな治療薬の開発が期待される。