Epigenetic approach to antifibrotic treatment for liver fibrosis

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K19364
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Gastroenterology
• Research Institution: Nara Medical University
• Principal Investigator: Kaji Kosuke 奈良県立医科大学, 医学部, 学内講師 (20623490)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: DNMT1

Outline of Final Research Achievements

This study aimed to develop a novel antifibtoric therapy targeting DNMT1. 5-azadC, a DNMT1 inhibitor, significantly inhibited proliferation and downregulated expressions of fibrotic markers in the activated hepatic stellate cells (Ac-HSC) in concentration dependent manners. Moreover, 5-azadC potently promoted a cellular senescence in Ac-HSCs. In murine models of liver fibrosis, 5-azadC suppressed a pathological liver fibrosis development with downregulation of hepatic expressions associated with profibrotic markers.
Comprehensive DNA methylation analysis elucidated that 5-azadC induced hypomethylation in CpG loci associated with TGF-β, NF-κB, and Cyclin D in the Ac-HSCs.Remarkably, 5-azadC induced demethylation in CpG loci associated with RASAL1 which is involved in persistent liver fibrosis development.

Free Research Field

肝線維化

Academic Significance and Societal Importance of the Research Achievements

肝疾患治療において肝線維化を直接抑制する治療法の開発は大きな課題であり、本研究ではDNMT1阻害によるメチル化制御を介した活性化肝星細胞の細胞老化を伴った新たな治療の可能性を見出した。また網羅的メチル化解析を行い、肝線維化治療の効果を予測し得る新規のエピジェネティックマーカーの開発に有用なデータ結果を見出した。本研究の結果から、“治療効果予測に基づく個別化医療”が可能となり、将来的に肝硬変患者の治療効果および予後を改善するのに大きく寄与するものと考える。