Prevention of NASH and NASH-related hepatocellular carcinoma by intrinsic anti-oxidative factor

• Project/Area Number: 17K08776
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Kurume University
• Principal Investigator: YOSHIDA TAKAFUMI 久留米大学, 医学部, 助教 (30368899)
• Co-Investigator(Kenkyū-buntansha): 秋葉 純 久留米大学, 大学病院, 教授 (00341305)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2018: ¥520,000 (Direct Cost: ¥400,000、Indirect Cost: ¥120,000); Fiscal Year 2017: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: NASH / 肝癌 / PEDF / AGEｓ / インフラマソーム / 非アルコール性肝炎 / AGEs / 酸化ストレス / Pyrotosis / 抗酸化因子 / 終末糖化産物 / アプタマー / 生体分子

Outline of Final Research Achievements

PEDF could slow the development and progression of steatohepatitis through the suppression of steatosis and oxidative stress in mice NASH model. In human tissues, the decreased expression of PEDF and the elevated expression of PEDF receptor was associated with aggressive properties of cancer. Moreover, NASH-related hepatic fibrosis and hepatocellular carcinoma were exacerbated in PEDF receptor transgenic mice. We furthermore demonstrated that AGEs-RAGE signaling promotes not only the progression of hepatic fibrosis and the development liver cancer in NASH through activation of inflammasome and pyrotosis. Our study suggests that PEDF supplementation and the blockade of AGEs-RAGE system may be a novel therapeutic strategy for the treatment of NASH.

Academic Significance and Societal Importance of the Research Achievements

非アルコール性肝炎(NASH:Non-alcoholic steatohepatitis)における生体内抗酸化因子の治療的役割を明らかにした。近年、増加の一途を辿りつつも有効な治療法のない非アルコール性肝炎に対して、本研究は新たな治療法の開発に貢献するものと考える。

Research Products

• [Journal Article] Pharmacokinetics and Safety of Single-Dose Esaxerenone in Japanese Subjects with Mild to Moderate Hepatic Impairment (2019)
  • Author(s): Kurata Akifumi、Yoshida Takafumi、Inoue Megumi、Ishizuka Tomoko、Nakatsu Takafumi、Shimizu Takako、Kato Manabu、Nishikawa Yasuhiro、Ishizuka Hitoshi
  • Journal Title: Advances in Therapy Volume: 37 Issue: 1 Pages: 253-264
  • DOI: 10.1007/s12325-019-01121-2
  • Peer Reviewed
• [Journal Article] Pigment Epithelium-Derived Factor (PEDF) Prevents Hepatic Fat Storage, Inflammation, and Fibrosis in Dietary Steatohepatitis of Mice (2017)
  • Author(s): Yoshida Takafumi、Akiba Jun、Matsui Takanori、Nakamura Kazuo、Hisamoto Takao、Abe Mitsuhiko、Ikezono Yu、Wada Fumitaka、Iwamoto Hideki、Nakamura Toru、Koga Hironori、Yamagishi Sho-ichi、Torimura Takuji
  • Journal Title: Digestive Diseases and Sciences Volume: 62 Issue: 6 Pages: 1527-1536
  • DOI: 10.1007/s10620-017-4550-x
  • Peer Reviewed
• [Journal Article] STAT3 deficiency prevents hepatocarcinogenesis and promotes biliary proliferation in thioacetamide-induced liver injury. (2017)
  • Author(s): Abe M, Yoshida T, Akiba J, Ikezono Y, Wada F, Masuda A, Sakaue T, Tanaka T, Iwamoto H, Nakamura T, Sata M, Koga H, Yoshimura A, Torimura T.
  • Journal Title: World J Gastroenterol Volume: 23 Issue: 37 Pages: 6833-6844
  • DOI: 10.3748/wjg.v23.i37.6833
  • Peer Reviewed / Open Access
• [Journal Article] Pancreatic Neuroendocrine Tumors and EMT Behavior Are Driven by the CSC Marker DCLK1 (2017)
  • Author(s): Yu Ikezono
  • Journal Title: Molecular Cancer Research Volume: 不明 Issue: 6 Pages: 744-752
  • DOI: 10.1158/1541-7786.mcr-16-0285
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] PEDF prevents hepatic fat storage, inflammation and fibrosis (2017)
  • Author(s): Takafumi Yoshida
  • Organizer: JDDW2017
  • Int'l Joint Research
• [Remarks] 久留米大学先端癌治療研究センター肝癌部門研究活動
  • URL: http://www.med.kurume-u.ac.jp/med/sentanca/kangan/