Elucidation of the molecular mechanisms of human non-alcoholic steatohepatitis (NASH)

• Project/Area Number: 16K01850
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Applied health science
• Research Institution: National Center for Global Health and Medicine
• Principal Investigator: Yasuda Kazuki 国立研究開発法人国立国際医療研究センター, その他部局等, その他 (80311611)
• Research Collaborator: Nammo Takao ; Funahashi Nobuaki
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: NASH / 生活習慣病 / mRNA / 遺伝子発現調節 / クラスター / AKR1B10 / miRNA / 非アルコール性脂肪性肝炎 / マイクロRNA

Outline of Final Research Achievements

We performed comprehensive analysis of transcriptome of the liver obtained from Japanese NASH (non-alcoholic steatohepatitis) subjects.
Unsupervised two-way cluster analyses revealed that genes with similar function, such as inflammation, lipid metabolism, cell profanation or fibrosis, constituted co-regulated gene clusters, which were quite compatible with “multiple parallel hits hypothesis” of NASH development. We analyzed mechanisms of transcriptional regulation of two interesting genes, AKR1B10 and a novel member of the same family AKR1B15, using human HuH7 cells, and found specific upstream signals for each gene, suggesting complex pathophysiology of NASH.

Academic Significance and Societal Importance of the Research Achievements

NASHは極めて頻度の高い疾患であるだけでなく、肝がんの発生母地として、また心血管病変のハイリスクとして重要であるが、病態の多くが不明で、侵襲的な肝生検以外に確定した診断方法がなく、さらに有効な治療薬もないなど、unmet medical needsの代表的疾患である。本研究は実際のヒト組織を用いてNASHの分子病態を明らかにし、画期的な診断・治療薬の開発への道を開く可能性を秘めた研究である。

Research Products

• [Journal Article] Non-invasive prediction of non-alcoholic steatohepatitis in Japanese patients with morbid obesity by artificial intelligence using rule extraction technology. (2018)
  • Author(s): Uehara D, Hayashi Y, Seki Y, Kakizaki S, Horiguchi N, Tojima H, Yamazaki Y, Sato K, Yasuda K, Yamada M, Uraoka T, Kasama K.
  • Journal Title: World J Hepatol. Volume: Dec 27;10(12) Issue: 12 Pages: 934-943
  • DOI: 10.4254/wjh.v10.i12.934
  • Peer Reviewed / Open Access
• [Journal Article] Genome-wide DNA methylation analysis during non-alcoholic steatohepatitis-related multistage hepatocarcinogenesis: comparison with hepatitis virus-related carcinogenesis. (2017)
  • Author(s): Kuramoto J, Arai E, Tian Y, Funahashi N, Hiramoto M, Nammo T, Nozaki Y, Takahashi Y, Ito N, Shibuya A, Ojima H, Sukeda A, Seki Y, Kasama K, Yasuda K, Kanai Y.
  • Journal Title: Carcinogenesis. Volume: 38 Issue: 3 Pages: 261-270
  • DOI: 10.1093/carcin/bgx005
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 肝細胞におけるAKR1B10の発現制御メカニズムの解析 (2018)
  • Author(s): 舟橋伸昭、宇田川陽秀、南茂隆生、安田和基
  • Organizer: 第61回日本糖尿病学会年次学術集会
• [Presentation] ヒトNASH肝で高発現するAKR1B15の発現制御機序および機能解析 (2018)
  • Author(s): 舟橋伸昭、宇田川陽秀、南茂隆生、安田和基
  • Organizer: 第5回肝臓と糖尿病・代謝研究会
• [Presentation] 日本人高度肥満症由来NASH肝のトランスクリプトーム解析 (2016)
  • Author(s): 舟橋伸昭、宇田川陽秀、南茂隆生、上番増喬、西村渉、平本正樹、松本健治、関洋介、笠間和典、安田和基
  • Organizer: 第3回肝臓と糖尿病・代謝研究会
  • Place of Presentation: 金沢
  • Year and Date: 2016-07-16