Direct Contribution of Mitochondorial Oxidative Stress to Hepatic Fibrogenesis

2013 Fiscal Year Final Research Report

• Project/Area Number: 24659376
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Gastroenterology
• Research Institution: Tokai University
• Principal Investigator: INAGAKI Yutaka 東海大学, 医学部, 教授 (80193548)
• Co-Investigator(Kenkyū-buntansha): ISHII Naoaki 東海大学, 医学部, 教授 (60096196)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Keywords: 酸化ストレス / 肝線維化 / マクロファージ

Research Abstract

Oxidative stress is considered to play a key role in the progression of chronic liver diseases. However, since production of oxidative stress may merely represent the consequences of cell damage and subsequent inflammation, it is virtually unknown whether oxidative stress is linked directly to fibrogenesis.
Hepatocytes isolated from Tet-mev-1 mouse, in which mitochondrial reactive oxygen species can be induced, exhibited decreased mitochondrial membrane potential. Tet-mev-1 mice were fed high fat/high sucrose (HFHS)diet, and microarray analyses indicated that CC chemokine expression was remarkably elevated in the liver tissue. However, the number of F4/80-positive cells was substantially decreased, and there was no
apparent liver fibrosis observed in Tet-mev-1 mice fed HFHS diet. These results suggested the important role of macrophages in the progression of liver fibrosis.

Research Products

• [Journal Article] Mechanisms of action of acetaldehyde in the up regulation of the humanα2(I) collagen gene in hepatic stellate cells-key roles of Ski, SMAD3, SMAD4 and SMAD7 (2014)
  • Author(s): Reyes-Gordillo K, Shah R, Arellanes- Robledo J, Hernández-Nazara Z, Rincón- Sánchez AR, Inagaki Y, Rojkind M, and Lakshman MR.
  • Journal Title: Am J Pathol 2014 Volume: (in press)
  • DOI: 10.1016/j.ajpath.2014.01.020
  • Peer Reviewed
• [Journal Article] A novel small compound accelerates dermal wound healing by modifying infiltration, proliferation and migration of distinct cellular components in mice (2014)
  • Author(s): Yamaoka H, Sumiyoshi H, Higashi K, Nakao S, Minakawa K, Sumida K, Saito K, Ikoma N, Mabuchi T, Ozawa A, and Inagaki Y.
  • Journal Title: J Dermatol Sci 2014 Volume: (in press)
  • DOI: 10.1016/j.jdermsci.2014.03.002
  • Peer Reviewed
• [Journal Article] Fibrogenesis and carcinogenesis in nonalcoholic steatohepatitis (NASH) : Involvement of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinase (TIMPs) (2014)
  • Author(s): Okazaki I, Noro T, Tsutsui N, Yamanouchi E, Kuroda H, Nakano M, Yokomori H, and Inagaki Y.
  • Journal Title: Cancers 2014 Volume: (in press)
  • Peer Reviewed
• [Journal Article] Stem and Progenitor Cell Systems in Liver Development and Regeneration (2014)
  • Author(s): Kamiya A and Inagaki Y.
  • Journal Title: Hepatol Res 2014 Volume: (in press)
  • Peer Reviewed
• [Journal Article] ERK-dependent downregulation of Skp2 reduces Myc activity with HGF, leading to inhibition of cell proliferation through a decrease in Id1 expression (2013)
  • Author(s): Li X, Bian Y, Takizawa Y, Hashimoto T, Ikoma T, Tanaka J, Kitamura N, Inagaki Y, Komada M, and Tanaka T.
  • Journal Title: Molecular Cancer Res Volume: 11 Pages: 1437-1447
  • DOI: 10.1158/1541-7786.MCR-12-0718
  • Peer Reviewed
• [Journal Article] Qualitative rather than quantitative changes are hallmarks of fibroblasts in bleomycin-induced pulmonary fibrosis (2013)
  • Author(s): Tsukui T, Ueha S, Abe J, Hashimoto S, Shichino S, Shimaoka T, Shand FHW, Arakawa Y, Oshima K, Hattori M, Inagaki Y, Tomura M, and Matsushima K.
  • Journal Title: Am J Pathol Volume: 183 Pages: 758-773
  • DOI: 10.1016/j.ajpath.2013.06.005
  • Peer Reviewed
• [Journal Article] Novel strategies for hepatocellular carcinoma based on MMPs science (2012)
  • Author(s): Okazaki I and Inagaki Y.
  • Journal Title: Anti-Cancer Agents Med Chem Volume: 12 Pages: 753-763
  • Peer Reviewed
• [Journal Article] Interplay between bone marrow and liver in the pathogenesis of hepatic fibrosis (2012)
  • Author(s): Inagaki Y and Higashiyama R.
  • Journal Title: Hepatol Res Volume: 42 Pages: 543-548
  • Peer Reviewed
• [Journal Article] Novel anti-fibrotic modalities for liver fibrosis : Molecular targeting and regenerative medicine in fibrosis therapy (2012)
  • Author(s): Inagaki Y, Higashiyama R, and Higashi K.
  • Journal Title: J Gastroenterol Hepatol Volume: 27 Pages: 85-88
  • Peer Reviewed
• [Presentation] Direct contribution of mitochondrial oxidative stress to hepatic fibrogenesis (2013)
  • Author(s): Moro T, Nakao S, Sumiyoshi H, Ishii T, Miyazawa M, Ishii N, and Inagaki Y.
  • Organizer: 64th Annual Meeting of the American Association for the Study of Liver Diseases
  • Place of Presentation: Washington DC
  • Year and Date: 2013-11-03
• [Presentation] Mitochondrial oxidative stress exacerbates inflammation and subsequent fibrogenesis in high fat diet-induced murine hepatic steatosis (2013)
  • Author(s): Moro T, Nakao S, Sumiyoshi H, Ishii T, Miyazawa M, Ishii N, and Inagaki Y.
  • Organizer: 17th International Symposium on Cells of the Hepatic Sinusoid
  • Place of Presentation: Osaka, Japan
  • Year and Date: 2013-09-25
• [Presentation] ミトコンドリア由来活性酸素惹起モデルマウスを用いた酸化ストレスによる肝線維化促進機序の解明 (2013)
  • Author(s): 茂呂忠、中尾祥絵、住吉秀明、宮沢正樹、石井恭正、石井直明、稲垣豊
  • Organizer: 第45回日本結合組織学会学術大会・第60回マトリックス研究会大会合同学術大会
  • Place of Presentation: 和歌山
  • Year and Date: 2013-06-28
• [Presentation] 線維肝の再生における骨髄と肝臓の臓器相関 (2012)
  • Author(s): 稲垣豊
  • Organizer: 第11回日本再生医療学会総会、シンポジウム5「臓器再生の名脇役達-血管再生と炎症・間質組織の生理学的および病理学的役割-」
  • Place of Presentation: 横浜
  • Year and Date: 2012-06-14
• [Remarks]
  • URL: http://www.med.u-tokai.ac.jp/daigakuin/pdf/inagaki_yutaka_2014_04_01.pdf
• [Remarks]
  • URL: http://www.med.u-tokai.ac.jp/daigakuin/web/matrix.html