Protective Effects of Peroxiredoxin 4 (PRDX4) on Metabolic Syndrome

• Project/Area Number: 16K08750
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Kanazawa Medical University (2017-2018); Kagoshima University (2016)
• Principal Investigator: YAMADA Sohsuke 金沢医科大学, 医学部, 教授 (90525453)
• Research Collaborator: TANIMOTO Akihide
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 抗酸化ストレス因子 / PRDX4 / メタボリックシンドローム / 予防 / NASH / 小腸機能 / アポトーシス / 炎症病理 / 動脈硬化 / 抗酸化ストレス / 腸内細菌

Outline of Final Research Achievements

The peroxiredoxin (PRDX) 4 is the only known secretory form and protects against oxidative damage by scavenging reactive oxygen species in both the intracellular compartments and the extracellular space. We generated unique human PRDX4 (hPRDX4) transgenic (Tg) mice and investigated the critical/diverse protective roles of PRDX4 against diabetes mellitus, atherosclerosis, insulin resistance, and nonalcoholic fatty liver disease (NAFLD) as well as evaluated its role in the intestinal function in various animal models. Our published data have shown that PRDX4 helps prevent the progression of metabolic syndrome by reducing local and systemic oxidative stress and synergistically suppressing steatosis, inflammatory reactions, and/or apoptotic activity. These observations suggest that Tg mice may be a useful animal model for studying the relevance of oxidative stress on inflammation and the dysregulation of lipid/bile acid/glucose metabolism upon the progression of human metabolic syndrome.

Academic Significance and Societal Importance of the Research Achievements

我々のグループでは、ヒトPRDX4 (hPRDX4)のトランスジェニックマウス(Tg)を独自に作製し、PRDX4が酸化ストレスおよび炎症性サイトカイン、アポトーシスを抑制し、メタボリックシンドローム回避に傾かせしめ得ることを解明してきた。これらの研究成果により、PRDX4の特殊性、特異性を際立たせることが可能となった。
これら我々の包括的な基礎研究が、将来的に臨床応用にまで結びつけば、非常に有意な独創性・社会的意義を持っていると確信される。

Research Products

• [Journal Article] The Association of Peroxiredoxin 4 with the Initiation and Progression of Hepatocellular Carcinoma. (2019)
  • Author(s): Guo X, Noguchi H, Ishii N, Homma T, Hamada T, Hiraki T, Zhang J, Matsuo K, Yokoyama S, Ishibashi H, Fukushige T, Kanekura T, Fujii J, Uramoto H, Tanimoto A,Yamada S.
  • Journal Title: Antioxid Redox Signal Volume: 30 Pages: 1271-1284
  • DOI: 10.1089/ars.2017.7426
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Protective Effects of Peroxiredoxin 4 (PRDX4) on Cholestatic Liver Injury. (2018)
  • Author(s): Zhang J, Guo X, Hamada T, Yokoyama S, Nakamura Y, Zheng J, Kurose N, Ishigaki Y, Uramoto H, Tanimoto A, Yamada S.
  • Journal Title: Int J Mol Sci. Volume: 19
  • DOI: 10.3390/ijms19092509
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Peroxiredoxin 4(PRDX4):Its critical in vivo roles in animal models of metabolic syndrome ranging from atherosclerosis to nonalcoholic fatty liver disease. (2018)
  • Author(s): Yamada Sohsuke、Gui Xin
  • Journal Title: Pathol Int. Volume: 68 Pages: 91-101
  • DOI: 10.1111/pin.12634
  • Peer Reviewed / Open Access
• [Journal Article] The Combination Of Weak Expression Of PRDX4 And Very High MIB-1 Labelling Index Independently Predicts Shorter Disease-free Survival In Stage I Lung Adenocarcinoma. (2018)
  • Author(s): Shioya A, Guo X, Motono N, Mizuguchi S, Kurose N, Nakada S, Aikawa A, Ikeda Y, Uramoto H, Yamada S.
  • Journal Title: Int J Med Sci. Volume: 15 Pages: 1025-1034
  • DOI: 10.7150/ijms.25734
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Cholic Acid Enhances Visceral Adiposity, Atherosclerosis and Nonalcoholic Fatty Liver Disease in Microminipigs (2017)
  • Author(s): Yamada S, Kawaguchi H, Yamada T, Guo X, Matsuo K, Hamada T, Miura N, Tasaki T, Tanimoto A.
  • Journal Title: J Atheroscler Thromb Volume: 24 Issue: 11 Pages: 1150-1166
  • DOI: 10.5551/jat.39909
  • NAID: 130006191597
  • ISSN: 1340-3478, 1880-3873
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 【血管生物学と疾患】日常業務でよく遭遇する血管病変の最新知見 粥状動脈硬化症の最新知見と病理 (2017)
  • Author(s): 谷本昭英、山田壮亮
  • Journal Title: 病理と臨床 Volume: 35 Pages: 700-706
  • Peer Reviewed / Open Access
• [Journal Article] マウスモデルおよび細胞培養と実験的粥状動脈硬化症 (2017)
  • Author(s): 山田壮亮
  • Journal Title: BIO Clinica Volume: 32 Pages: 53-58
  • Peer Reviewed / Open Access
• [Journal Article] Overexpression of Peroxiredoxin 4 Induces Adaptive Intestinal Lipid Metabolism Associated with Suppressive Nonalcoholic Steatohepatitis in a Dietary Mouse Model. (2016)
  • Author(s): Aya Nawata, Hirotsugu Noguchi, Yuichi Mazaki, Toshihiro Kurahashi, Atsunori Nabeshima, Ke-Yong Wang, Satoshi Kimura, Hidetaka Uramoto, Kimitoshi Kohno, Hatsumi Taniguchi, Yoshiya Tanaka, Junichi Fujii, Yasuyuki Sasaguri Toshiyuki Nakayama, and Sohsuke Yamada.
  • Journal Title: PLoS One Volume: e0152549
  • DOI: 10.1371/journal.pone.0152549
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 動脈硬化からメタボリックシンドロームへ～遺伝子改変動物モデルを用いた病理組織的検討～ (2018)
  • Author(s): 山田壮亮
  • Organizer: 第１０７回日本病理学会総会 札幌
• [Presentation] The Association of Peroxiredoxin 4 with the Initiation and Progression of Hepatocellular Carcinoma. (2018)
  • Author(s): Sohsuke Yamada
  • Organizer: Forum on Taiwan-Japan Clinical Research and Application of Regenerative Medicine
  • Int'l Joint Research
• [Presentation] 抗酸化酵素ペルオキシレドキシン(PRDX)4とmetabolic syndrome (2017)
  • Author(s): 山田壮亮
  • Organizer: 第14回日本病理学会カンファレンス
• [Presentation] 遺伝子改変動物モデルを用いた、動脈硬化における炎症病理学的検討 (2017)
  • Author(s): 山田壮亮
  • Organizer: 第63回日本病理学会秋期特別総会
• [Presentation] An Outside-In Signaling by Cuff-Injury Induces Vascular Remodeling Mimicking (2017)
  • Author(s): 山田壮亮
  • Organizer: 第49回日本動脈硬化学会総会・学術集会
• [Presentation] Cholic Acid Induces Systemic Macrophage Mobilization and Enhances Visceral A diposity, Atherosclerosis and Non-alcoholic Fatty Liver Disease in a High Fa t/High Cholesterol Diet-fed Microminipig (2017)
  • Author(s): 山田壮亮
  • Organizer: 第49回日本動脈硬化学会総会・学術集会
• [Presentation] Critical In Vivo Roles of Histamine and Histamine Receptor Signaling in Animal Models of Metabolic Syndrome (2017)
  • Author(s): 山田壮亮
  • Organizer: 第46回日本心脈管作動物質学会年会
• [Presentation] Critical and Diverse In Vivo Roles of Apoptosis Signal-regulating Kinase 1 in Animal Models of Atherosclerosis and Cholestatic Liver Injury (2017)
  • Author(s): 山田壮亮
  • Organizer: 第46回日本心脈管作動物質学会年会
• [Presentation] An Outside-In Signaling by Cuff-Injury Induces Vascular Remodeling Mimicking Triglyceride Deposit Cardiomyovasculopathy (2017)
  • Author(s): 山田壮亮
  • Organizer: 第46回日本心脈管作動物質学会年会
• [Presentation] コール酸はマイクロミニピッグのメタボリックシンドロームにおけるユニークな表現型を誘引する (2017)
  • Author(s): 山田壮亮
  • Organizer: 第106回日本病理学会総会
• [Presentation] メタボリックシンドローム動物モデルにおける、ヒスタミン・ヒスタミン受容体シグナリングの重要な役割Critical Roles of Histamine and its Receptor Signaling in Animal Models of Metabolic Syndrome (2017)
  • Author(s): 山田壮亮
  • Organizer: 第106回日本病理学会総会
• [Presentation] PRDX4 overexpression induces an adaptive intestinal lipid metabolism in a NAFLD mouse model. (2016)
  • Author(s): Yamada S, Nawata A, Noguchi H, Wang KY, Nakayama T, Sasaguri Y.
  • Organizer: 第105回日本病理学会総会、仙台
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2016-05-12