Role of tissue fibrinolytic factors in NASH liver fibrosis and intrahepatic macrophage activation

• Project/Area Number: 17K10666
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Hamamatsu University School of Medicine
• Principal Investigator: Iwaki Takayuki 浜松医科大学, 医学部, 准教授 (70509463)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: LDL / apoB100 / Macrophage / Foam cell / NASH / Fibrosis / 線溶因子 / ヒト型高脂血症 / 四塩化炭素 / BCG / マクロファージ / 組織線溶

Outline of Final Research Achievements

L-/-/A-/- mouse model is characterized as spontaneous LDL-C driven atherosclerosis model. We have established a NASH model by using L-/-/A-/- mouse model, in which hepatic foam cell formation of macrophages were observed with massive fibrosis.
Since the LDL fraction is hardly observed as a lipoprotein fraction in Wt mice, it will be possible to evaluate the effect of LDL on NASH pathology in our murine system. For the next steps, we are planning to evaluate the effects on cells modified by LDL, especially macrophages, in connection with coagulation/fibrinolytic factors.

Academic Significance and Societal Importance of the Research Achievements

今回作製したNASHモデルは顕著な高LDL血症を示す実験モデルであり、従来のモデルでは評価できないLDLによる病態への影響を評価することが可能となっている。今後NASHにおけるLDLコレステロールの影響に関して本モデルを用いて研究することで、現在有効な治療薬が存在しないNASHにおける有望な治療薬が開発される可能性がある。

Research Products

• [Journal Article] Hyperfunctioning Papillary Thyroid Carcinoma with a BRAF Mutation: The First Case Report and a Literature Review (2021)
  • Author(s): Shinkai S, Ohba K, Kakudo K, Iwaki T, Mimura Y, Matsushita A, Kuroda G, Sakai Y, Nishino N, Umemura K, Suda T, Sasaki S
  • Journal Title: European Thyroid Journal Volume: - Issue: 3 Pages: 262-267
  • DOI: 10.1159/000513552
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Nanobody production can be simplified by direct secretion from Escherichia coli (2020)
  • Author(s): Iwaki T, Hara K, Umemura K.
  • Journal Title: Protein Expr Purif Volume: 170 Pages: 105607-105607
  • DOI: 10.1016/j.pep.2020.105607
  • Peer Reviewed
• [Journal Article] Recognition of Plasminogen Activator Inhibitor Type 1 as the Primary Regulator of Fibrinolysis (2019)
  • Author(s): Urano T, Suzuki Y, Iwaki T, Sano H, Honkura N, Castellino FJ.
  • Journal Title: Curr Drug Targets. Volume: 20 Issue: 16 Pages: 1695-1701
  • DOI: 10.2174/1389450120666190715102510
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Characterization of Atherosclerosis Formation in a Murine Model of Type IIa Human Familial Hypercholesterolemia. (2018)
  • Author(s): Miyajima C, Iwaki T, Umemura K, Ploplis VA, Castellino FJ
  • Journal Title: Biomed Res Int Volume: - Pages: 1878964-1878964
  • DOI: 10.1155/2018/1878964
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Elevated Plasma Levels of LDL Cholesterol Promote Dissecting Thoracic Aortic Aneurysms in Angiotensin II-Induced Mice. (2018)
  • Author(s): Tanaka H, Iida Y, Iwaki T, Suzuki Y, Sano H, Miyajima C, Zaima N, Sasaki T, Sumioka A, Hakamata S, Shimizu H, Umemura K, Urano T.
  • Journal Title: Ann Vasc Surg. Volume: 48 Pages: 204-213
  • DOI: 10.1016/j.avsg.2017.10.006
  • Peer Reviewed
• [Journal Article] Mutation in a highly conserved glycine residue in strand 5B of plasminogen activator inhibitor 1 causes polymerization. (2017)
  • Author(s): Iwaki T, Nagahashi K, Takano K, Suzuki-Inoue K, Kanayama N, Umemura K, Urano T.
  • Journal Title: Thrombosis and Haemostasis Volume: 117(5) Issue: 05 Pages: 860-869
  • DOI: 10.1160/th16-07-0572
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Successful synthesis of active human coagulation factor VII by co-expression of mammalian gamma-glutamyl carboxylase and modification of vit.K cycle in Drosophila Schneider S2 cells (2017)
  • Author(s): Nagahashi, K. Umemura, K. Kanayama, N. Iwaki, T.
  • Journal Title: Cytotechnology Volume: 69 Issue: 2 Pages: 317-327
  • DOI: 10.1007/s10616-016-0059-y
  • Peer Reviewed
• [Journal Article] Lysophosphatidylcholine Acyltransferase-3 Expression Is Associated with Atherosclerosis Progression. (2017)
  • Author(s): Tanaka H, Zaima N, Sasaki T, Yamamoto N, Inuzuka K, Yata T, Iwaki T, Umemura K, Sano H, Suzuki Y, Urano T, Setou M, Unno N
  • Journal Title: J Vasc Res Volume: 54(4) Issue: 4 Pages: 200-208
  • DOI: 10.1159/000473879
  • Peer Reviewed
• [Presentation] 慢性骨髄性白血病患者におけるイマチニブ休薬後の血清コレステロール値の上昇 (2021)
  • Author(s): 高羽 理光、小野 孝明、岩城 孝行、梅村 和夫
  • Organizer: 第94回日本薬理学会年会
• [Presentation] 高コレステロール血症はくも膜下出血を減弱する可能性 (2021)
  • Author(s): 外村 和也、牧野 洋、岩城 孝行、今井 亮、木村 哲朗、中島 芳樹、梅村 和夫
  • Organizer: 第94回日本薬理学会年会
• [Presentation] Ⅱa型家族性高脂血症における組織型プラスミノゲン活性化因子の役割 (2021)
  • Author(s): 荒川 友博、岩城 孝行、高羽 理光、梅村 和夫
  • Organizer: 第94回日本薬理学会年会
• [Presentation] IIa型高脂血症モデルであるLdlr-/-/Apobec1-/- (L-/-/A-/-）マウスにおける動脈硬化症と血液凝固線溶因子の関係 (2018)
  • Author(s): 岩城 孝行
  • Organizer: 第50回日本動脈硬化学会
  • Invited
• [Presentation] 最近のPAI-1の話題 (2018)
  • Author(s): 岩城 孝行
  • Organizer: 第3回黒潮カンファレンス
• [Presentation] A mutation of highly conserved glycine in strand 5B of plasminogen activator inhibitor 1 caused its deficiency due to self-polymerization, which was also observed in other serine proteinase inhibitors. (2017)
  • Author(s): 岩城孝行
  • Organizer: 第39回日本血栓止血学会学術集会