NASH induced-liver fibrosis was mediated by the disruption of circadian clock system

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K06536
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
• Research Institution: Nihon University
• Principal Investigator: WADA Taira 日本大学, 薬学部, 准教授 (20597398)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: NASH / 線維化 / 体内時計

Outline of Final Research Achievements

In this study, we examined the development of NASH and exacerbation of fibrosis by using hepatocyte-specific deletion of the clock gene BMAL1 (HKO) mice. The diurnal variation in liver injury, inflammation, and fibrosis were higher during light hours and lower during dark hours in Control mice fed a NASH-inducing diet. However, those diurnal variation were not observed in HKO　mice. Moreover, the diurnal variation in NASH fibrosis was implicated in TGFβ1 protein expression. Furthermore, HKO mice showed exacerbated progression to NASH-induced hepatocarcinoma.　These results indicate molecular clock system mediated by BMAL1 is associated with the development of NASH and exacerbation of fibrosis.

Free Research Field

生物系薬学

Academic Significance and Societal Importance of the Research Achievements

NASHは、肥満や2型糖尿病を背景に線維化を伴って発症し、肝硬変、肝がんへと進展する代謝性疾患であり、近年、その有病率が増加している。線維化の進展は、NASHの予後と強い相関性を示すが、線維化の機序については未知な部分が多い。近年、生活習慣の変化に伴う体内時計の変調が代謝性疾患発症リスクとして注視されている。本研究成果は、体内時計の変調に起因した線維化の新たなメカニズムを示す知見である。