Development of identification of the ER stress to be involved in non-alcoholic fatty liver disease and the new therapy

• Project/Area Number: 16K19343
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Gastroenterology
• Research Institution: Tottori University
• Principal Investigator: MATONO TOMOMITSU 鳥取大学, 医学部附属病院, 助教 (60571841)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 非アルコール性脂肪肝炎 / ERストレス / NASH / FLS

Outline of Final Research Achievements

The aim of this study is to clarify that ER stress is involved in NASH. We confirmed the expression of ER stress in liver tissue of FLS and FLS-ob/ob model mouse. We analyzed the gene expression of ER stress by using RT-PCR.　Severe steatohepatitis was detected in 24 and 36 weeks in FLS-ob/ob mouse and liver fibrosis at 36 weeks of age, 48 weeks of age respectively. The gene expression of Tgfb1, Colla1 and Timp-1 significantly increased at 24, 36 and 48 weeks compared with FLS mouse. The gene expression of Tgfb1 and Timp-1 increased as a week of age advanced. The gene expression of Atf3, Nupr1 and C-jun significantly increased at 24, 36 and 48 weeks compared with FLS mouse. It was found that ER stress was involved in clinical condition extension of NASH, and likelihood to clinical application was suggested.

Academic Significance and Societal Importance of the Research Achievements

近年、非アルコール性脂肪肝炎の病態進展に小胞体ストレスの関与が報告されているが、本研究は、FLS-ob/obマウスを用いて、非アルコール性脂肪肝炎における小胞体ストレスの役割について明らかにしたものである。非アルコール性脂肪肝炎マウスでの肝線維化進展にAtf3、Nupr1、C-jun遺伝子発現が増加し、さらにアポトーシスが深く関与している可能性が示唆された。本研究は、非アルコール性脂肪肝炎において、小胞体ストレス遺伝子であるAtf3、Nupr1、C-jun遺伝子が肝線維化や炎症などの病態形成に関与する新たな知見であり、将来的に非アルコール性脂肪肝炎の創薬に繋がる可能性がある。

Research Products

• [Journal Article] Gene Expression Analysis of the Activating Factor 3/Nuclear Protein 1 Axis in a Non-alcoholic Steatohepatitis Mouse Model. (2019)
  • Author(s): Nagahara R, Matono T, Sugihara T, Matsuki Y, Yamane M, Okamoto T, Miyoshi K, Nagahara T, Okano JI, Koda M, Isomoto H.
  • Journal Title: Yonago Acta Medica Volume: 62 Pages: 36-46
  • NAID: 130007626303
  • Peer Reviewed / Open Access
• [Journal Article] Protective Effects of Ipragliflozin, a Sodium-glucose Cotransporter 2 Inhibitor, on a Non-alcoholic Steatohepatitis Mouse Model. (2019)
  • Author(s): Yamane M, Matono T, Okano JI, Nagahara R, Matsuki Y, Okamoto T, Miyoshi KI, Sugihara T, Nagahara T, Koda M, Isomoto H.
  • Journal Title: Yonago Acta Medica Volume: 62 Pages: 30-35
  • NAID: 130007626275
  • Peer Reviewed
• [Presentation] NAFLDモデルマウス(FLS、FLS-ob/ob)の肝線維化進展とERストレスの関連 (2018)
  • Author(s): 永原 蘭、的野智光、孝田雅彦、松木由佳子、山根昌史、岡本敏明、三好謙一、杉原誉明、大山賢治、法正恵子、岡野淳一、磯本 一
  • Organizer: 第54回日本肝臓学会総会
• [Presentation] The involvement of endoplasmic reticulum stress in the progression of hepatic fibrosis and carcinogenesis in non-alcoholic steatohepatitis mice (2018)
  • Author(s): Tomomitsu Matono, Ran Nagahara, Yukako Matsuki, Masafumi Yamane, Toshiaki Okamoto, Ken-ichi Miyoshi, Takaaki Sugihara, Takakazu Sugihara, Kenji Oyama, Keiko Hosho, Jun-ichi Okano, Masahiko Koda, Hajime Isomoto
  • Organizer: AASLD 2018