Unraveling the Pathophysiology of NASH through Changes in LipoQuality

2023 Fiscal Year Final Research Report

• Project/Area Number: 21H02892
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Mie University
• Principal Investigator: Nakagawa Hayato 三重大学, 医学系研究科, 教授 (00555609)
• Co-Investigator(Kenkyū-buntansha): 工藤 洋太郎 東京大学, 医学部附属病院, 助教 (90608358)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 非アルコール性脂肪性肝疾患 / リン脂質代謝 / 脂質生合成経路

Outline of Final Research Achievements

Enhanced de novo lipogenesis mediated by SREBP is thought to be involved in nonalcoholic steatohepatitis (NASH) pathogenesis. In this study, we assessed the impact of SREBP inhibition on NASH and liver cancer development in murine models. Unexpectedly, SREBP inhibition via deletion of SCAP in the liver exacerbated liver injury, fibrosis, and carcinogenesis, despite markedly reduced hepatic steatosis. SCAP-SREBP pathway inhibition altered the fatty acid (FA) composition of phosphatidylcholines due to both impaired FA synthesis and disorganized FA incorporation into phosphatidylcholine via LPCAT3 downregulation, which led to endoplasmic reticulum stress and hepatocyte injury. Thus, excessively strong and broad lipogenesis inhibition was counterproductive for NASH therapy, which will have important clinical implications in NASH treatment.

Free Research Field

消化器病学

Academic Significance and Societal Importance of the Research Achievements

本研究結果から、進行したburned-out NASH で生じているSREBP を介した脂質生合成機能低下は、リン脂質組成の変化を介して病態進行を促進している可能性があり、リン脂質の補充や脂肪酸組み込み異常の是正が、進行NASH の治療法の一つとなる可能性が示唆された。また現在NASH に対して脂質生合成酵素を標的とした薬剤の開発が盛んに行われているが、過剰かつ広範な脂質生合成阻害はかえって病態を悪化させる可能性もあることがわかり、このことは今後の薬剤開発において重要な示唆を与えると思われる。