Involvement of RIG-I-like receptors in the pathogenesis of NAFLD

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K08349
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Hirosaki University
• Principal Investigator: Kawaguchi Shogo 弘前大学, 医学研究科, 助教 (90455741)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: MDA5 / RIG-I / NASH / NAFLD / マクロファージ

Outline of Final Research Achievements

Retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) are pattern recognition receptors for intracellular nucleic acids. The RLRs, consist of RIG-I and melanoma differentiation-associated gene 5 (MDA5), are involved in innate immune responses. In the present study, we investigated the expression of RLRs in the liver of NAFLD patients and diet-induced NASH model mice. The results demonstrated that MDA5-positive cells was increased in the NAFLD patient. The cells expressed CD68 and CD11b, suggesting they were infiltrating macrophages. The mRNA level of MDA5 was increased prior to the enhanced expression of pro-inflammatory cytokines. Stimulation with lipopolysaccharide leaded to the increased expression of MDA5 in macrophages, suggesting that gut microbiota-derived antigen plays a critical role in the hepatic induction of MDA5.

Free Research Field

消化器病学

Academic Significance and Societal Importance of the Research Achievements

NASHは世界的に患者数が増加している疾患であり、肝硬変、肝細胞癌の原因となるばかりでなく、脳心血管疾患の発症にも関連するため重要な疾患である。本邦においては減量と糖尿病などの併存疾患に対する治療が中心であり、根本的治療法の開発のためには病態解明による新規治療標的の同定が不可欠である。本研究では、NASH病態進展機序の一つに自然免疫応答のメカニズムが関与することに着目し、これまで報告がなかったRLRs分子の病態への関与を明らかにした。とくにMDA5はサイトカインを高産生する活性化マクロファージに発現しており、NASHの新規治療標的となる可能性が示唆された。