Analysis of mechanisms of anti-HCV drug ribavirin-induced downregulation of C/EBPalpha and establishment of drug screening system for suppression of neutral lipid synthesis

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K07972
• 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: Okayama University
• Principal Investigator: Satoh Shinya 岡山大学, 医歯薬学総合研究科, 助教 (80333558)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: C/EBPα / リバビリン / GPAM / 中性脂肪量 / トリグリセリド合成

Outline of Final Research Achievements

We have previously demonstrated that anti-hepatitis C virus drug ribavirin reduces the amount of intracellular neutral lipids. In this study, we revealed that ribavirin-induced downregulation of C/EBPα and SREBP1c reduced the level of GPAM, which is one of the limiting enzymes of triglyceride synthesis, leading to the reduction in the intracellular neutral lipids. We also revealed the mechanism of the regulation of GPAM expression by C/EBPα, in which C/EBPα functions as the distal enhancer to maintain an open chromatin structure at C/EBPα binding regions in the GPAM genome.
Furthermore, by using the cell-based assay system monitoring the level of exogenously expressed C/EBPα protein, which was developed by us, and kinase screening library, we found mTOR-inhibitors reduced the level of C/EBPα protein, suggesting that mTOR contributes to sustaining C/EBPα protein level.

Free Research Field

肝臓学　ウイルス学　分子生物学

Academic Significance and Societal Importance of the Research Achievements

本研究で解明したトリグリセリド合成律速酵素であるGPAMの遺伝子発現制御機序では、C/EBPαが遠位のエンハンサーとして働き、GPAMゲノムDNAの構造変化を誘引し活性化することを初めて示した。
肝細胞での中性脂肪合成の亢進は脂肪肝、肝がんの発症リスクを高める。従って、本研究で得られた知見は中性脂肪合成を抑制する治療法や薬剤開発に貢献すると考えられ、肝病態発症の予防、改善に恩恵を与える。また、中性脂肪合成の亢進は、肝がんのみならず他組織でのがん発生、悪性化にも関わっており、組織の垣根を越えた抗がん作用の開発につながることが期待される。