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Molecular mechanisms of disturbance in cell survival system by alcohol abuse

Research Project

Project/Area Number 16390196
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Legal medicine
Research InstitutionSapporo Medical University

Principal Investigator

MATSUMOTO Hiroshi  Sapporo Medical University, School of Medicine, Professor (60263092)

Co-Investigator(Kenkyū-buntansha) NISHITANI Yoko  Sapporo Medical University, School of Medicine, Instructor (30359997)
FUJII Kenichi  Sapporo Medical University, School of Medicine, Instructor (60419661)
IMABAYASHI Kiyomi  Sapporo Medical University, School of Medicine, Instructor (50419660)
Project Period (FY) 2004 – 2005
Project Status Completed (Fiscal Year 2005)
Budget Amount *help
¥13,100,000 (Direct Cost: ¥13,100,000)
Fiscal Year 2005: ¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2004: ¥9,400,000 (Direct Cost: ¥9,400,000)
Keywordsalcohol / NF-kappaB / JNK / Akt / SREBP / TLR4 / polyunsaturated fatty acid / NAFLD / CYP2E1 / PPAR / NF-KappaB / SREBP
Research Abstract

1. Activations of JNK and Akt were enhanced by co-treatment with ethanol and a classical inhibitor of alcohol dehydrogenase (ADH). Addition of an anti- oxidant reduced the activation of JNK. Ethanol loading with ADH inhibition causes down-regulation of GRP78 mRNA levels. Therefore, these findings suggest first revelation that inhibition of ethanol metabolism complicates oxidative and ER stresses produced by ethanol..
2. The development of nonalcoholic fatty liver was not associated with insulin resistance but involves suppression of SREBP-1c. This suggests an activator of SREBP-1c may induce the progression of steatosis to steatohepatitis. Since NF- κB inhibitors reduced the steatosis as well as PPAR agonists and then decreased endoplasmic reticulum stress, they may be also effective in ameliorating NAFLD.
3. Fish oil feeding caused inflammation in the liver and induced proinflammatory cytokines, PPARs, CYP4As, and CYP2E1. Fish oil contains rich polyunsaturated fatty acids. These findings suggest that polyunsaturated fatty acid plays a crucial role in development of alcoholic and nonalcoholic fatty liver disease.
4. Hindlimb unloading caused elevating portal endotoxin levels, but did not cause sever liver injury. Acute ethanol treatment for the hindlimb unloading model induced disturbance in proinflammmatory response via TLR4 signalling.

Report

(3 results)
  • 2005 Annual Research Report   Final Research Report Summary
  • 2004 Annual Research Report
  • Research Products

    (32 results)

All 2009 2008 2007 2006 2005 2004 2003 Other

All Journal Article (18 results) (of which Peer Reviewed: 8 results) Presentation (14 results)

  • [Journal Article] Prior ethanol injection promotes brain edema after traumatic brain injury : evidence for poor prognosis for intoxicated patients2009

    • Author(s)
      Katada R, Nishitani Y, Honmou O, Okazaki S, Houkin K, Matsumoto H
    • Journal Title

      J Neurotrauma 26

      Pages: 2015-2025

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Femoral head osteonecrosis can be caused by disruption of the systemic immune response via the toll-like receptor 4 signalling pathway2009

    • Author(s)
      Okazaki S, Nishitani Y, Nagoya S, Kaya M, Yamashita T, Matsumoto H
    • Journal Title

      Rheumatology 48

      Pages: 227-232

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Prior ethanol injection promotes brain edema after traumatic brain injury : evidence for poor prognosis for intoxicated patients2009

    • Author(s)
      Katada R, Nishitani Y, Honmou O, Okazaki S, Houkin K, Matsumoto H.
    • Journal Title

      J Neurotrauma 26

      Pages: 2015-2025

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Femoral head osteonecrosis can be caused by disruption of the systemic immune response via the toll-like receptor 4 signalling pathway2009

    • Author(s)
      Okazaki S, Nishitani Y, Nagoya S, Kaya M, Yamashita T, Matsumoto H.
    • Journal Title

      Rheumatology 48

      Pages: 227-232

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Ethanol-induced JNK activation is suppressed via active Akt in hepatocytes2008

    • Author(s)
      Nishitani Y, Okazaki S, Imabayashi K, Katada R, Matsumoto H
    • Journal Title

      Jpn.J.Alcohol & Drug Dependence 43

      Pages: 35-43

    • NAID

      10024163712

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Ethanol-induced JNK activation is suppressed via active Akt in hepatocytes2008

    • Author(s)
      Nishitani Y, Okazaki S, Imabayashi K, Katada R, Matsumoto H.
    • Journal Title

      Jpn J Alcohol & Drug Dependence 43

      Pages: 35-43

    • NAID

      10024163712

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Saturated and monounsaturated fatty acids increase interleukin-10 production in rat hepatocytes.2007

    • Author(s)
      Nishitani Y, Okazaki S, Imabayashi K, Katada R, Umetani K, Yajima H, Matsumoto H
    • Journal Title

      Jpn.J.Alcohol & Drug Dependence 42

      Pages: 32-35

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Saturated and monounsaturated fatty acids increase interleukin-10 production in rat hepatocytes2007

    • Author(s)
      Nishitani Y, Okazaki S, Imabayashi K, Katada R, Umetani K, Yajima H, Matsumoto H.
    • Journal Title

      Jpn.J.Alcohol & Drug Dependence 42

      Pages: 32-35

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Ethanol rapidly causes activation of JNK associated with ER stress under inhibition of ADH2006

    • Author(s)
      Nishitani Y, Matsumoto H.
    • Journal Title

      FEBS Lett 580

      Pages: 9-14

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Relationship between activation of NF-kappaB and liver injury in hindlimb unloading rats2005

    • Author(s)
      Okazaki S, Nishitani Y, Fujii K, Matsumoto H.
    • Journal Title

      Alcohol Biomed Res 25

      Pages: 34-37

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Mechanisms of JNK activation by ethanol under ADH-inhibitor treatment2004

    • Author(s)
      Nishitani Y, Fujii K, Matsumoto H
    • Journal Title

      Alcohol Biomed Res 24

      Pages: 57-60

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Mechanisms of JNK activation by ethanol under ADH-inhibitor treatment2004

    • Author(s)
      Nishitani Y, Fujii K, Matsumoto H.
    • Journal Title

      Alcohol Biomed Res 24

      Pages: 57-60

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Effects of peroxisome proliferator-activated receptor agonists on murine nonalcoholic liver injury2004

    • Author(s)
      Fujii K, Nishitani Y, Matsumoto H.
    • Journal Title

      Alcohol Biomed Res 24

      Pages: 93-97

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Effects of peroxisome proliferator-activated receptor agonists on murine nonalcoholic liver injury2003

    • Author(s)
      Fujii K, Nishitani Y, Matsumoto H
    • Journal Title

      Alcohol Biomed Res 24

      Pages: 93-97

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] SNF-B Inhibitors Suppress SREBP-2 and GRP78 Expression and Prevent Progression of Dietary Non-Alcoholic Fatty Liver Disease in Mice

    • Author(s)
      Fujii K, Nishitani Y, Okazaki S, Shinomura Y, Imai K, Matsumoto H.
    • Journal Title

      (in submission)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Ethanol-induced NF-kappaB activation occurs via PKA- and PKC-independent pathways in the liver

    • Author(s)
      Matsumoto H, Nishitani Y, Fujii K, Okazaki S, Umetani K, Imabayashi K, Yajima H, Katada R.
    • Journal Title

      (in submission)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Effect of ALDH2 inhibition on urinary 5-HTOL/5-HIAA, a marker of recent drinking : a pharmacokinetic study in rats

    • Author(s)
      Umetani K, Matsumoto H.
    • Journal Title

      (in submission)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Hindlimb unloading alters ethanol-induced proinflammatory responses in the liver and soleus muscle of rats

    • Author(s)
      Okazaki S, Nishitani Y, Fujii K, Yamashita Y, Matsumoto H.
    • Journal Title

      (in submission)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Presentation] Role of TLR4 in development of nonalcoholic fatty liver disease2005

    • Author(s)
      Matsumoto H, Fujii K, Nishitani Y, Okazaki S, Yajima H.
    • Organizer
      28th Annual Meeting of the Research Society on Alcoholism
    • Place of Presentation
      Santa Barbara, U.S.A.
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Presentation] Hindlimb uploading do not induce liver injury via elevated portal LPS which is one mechanism of pathogenesis of alcoholic liver disease2005

    • Author(s)
      Okazaki S, Nishitani Y, Fujii K, Umetani K, Yajima H, Matsumoto H.
    • Organizer
      28th Annual Meeting of the Research Society on Alcoholism
    • Place of Presentation
      Santa Barbara, U.S.A.
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Presentation] Dietary fatty acids play an important role in development of nonalcoholic fatty liver disease2005

    • Author(s)
      Fujii K, Nishitani Y, Okazaki S, Umetani K, Imai K, Matsumoto H.
    • Organizer
      28th Annual Meeting of the Research Society on Alcoholism
    • Place of Presentation
      Santa Barbara, U.S.A.
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Presentation] Role of dietary oils in the progress of nonalcoholic fatty liver disease in mice2005

    • Author(s)
      Fujii K, Nishitani Y, Okazaki S, Umetani K, Imabayashi K, Yajima H, Katada R, Imai K, Matsumoto H.
    • Organizer
      SFRBM's 12th Annual Meeting
    • Place of Presentation
      Austin, U.S.A.
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Presentation] Effects of hindlimb unloading on hepatic inflammatory response in rats2005

    • Author(s)
      Okazaki S, Fujii K, Nishitani Y, Umetani K, Imabayashi K, Yajima J, Katada R, Matsumoto H.
    • Organizer
      SFRBM's 12th Annual Meeting
    • Place of Presentation
      Austin, U.S.A.
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Presentation] Contribusion of TLR4 to the pathogenesis of nonalcoholic fatty liver disease2005

    • Author(s)
      Matsumoto H, Fujii K, Nishitani Y, Okazaki S, Imabayashi K, Yajima H, Katada R.
    • Organizer
      SFRBM's 12th Annual Meeting
    • Place of Presentation
      Austin, U.S.A.
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Presentation] Role of Dietary oils in the development of nonalcoholic fatty liver disease in mice2005

    • Author(s)
      Matsumoto H, Fujii K.
    • Organizer
      The 3rd Science and Research Symposim Key Topic 2005 : Haptitis and Liver fibrosis-from Basic Research to the Clinic
    • Place of Presentation
      Nagoya
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Presentation] Role of ethanol in the Myd88-independent toll-like receptor signaling pathway2004

    • Author(s)
      Matsumoto H, Nishitani Y, Fujii K.
    • Organizer
      The 12th World Congress on Biomedical Alcohol Research of The International Society for Biomedical Research on Alcoholism. Alcohol Clin Exp Res
    • Place of Presentation
      Heidelberg/Mannheim, Germany
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Presentation] TLR4 signaling progresses fatty liver? -Evidence from TLR4-mutant mice fed with methionine- and choline-deficient diet2004

    • Author(s)
      Matsumoto H, Fujii K, Nishitani Y.
    • Organizer
      The 12th World Congress on Biomedical Alcohol Research of The International Society for Biomedical Research on Alcoholism. Alcohol Clin Exp Res
    • Place of Presentation
      Heidelberg/Mannheim, Germany
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Presentation] Effects of peroxisome proliferator-activated receptor agonists on nurine nonalcoholic liver injury2004

    • Author(s)
      Fujii K, Nishitani Y, Matsumoto H.
    • Organizer
      The 12th World Congress on Biomedical Alcohol Research of The International Society for Biomedical Research on Alcoholism. Alcohol Clin Exp Res
    • Place of Presentation
      Heidelberg/Mannheim, Germany
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Presentation] Regulation of activated Akt in JNK activation under ethanol loading2004

    • Author(s)
      Nishitani Y, Fujii K, Matsumoto H.
    • Organizer
      The 12th World Congress on Biomedical Alcohol Research of The International Society for Biomedical Research on Alcoholism. Alcohol Clin Exp Res
    • Place of Presentation
      Heidelberg/Mannheim, Germany
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Presentation] Role of Myd88-independent signalling pathway in ethanol induced NF-kappaB activation2004

    • Author(s)
      Matsumoto H, Nishitani Y, Okazaki S, Umetani K, Fujii K.
    • Organizer
      The 11th Annual Meeting of the Society for Free Radical Biology and Medicine Free Radical Biol Med
    • Place of Presentation
      St.Thomas, U.S.A.
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Presentation] Role of mitochondrial signals in the activation of c-Jun N-terminal kinase and NF-kappaB by ethanol2004

    • Author(s)
      Matsumoto H, Nishitani Y, Okazaki S, Umetani K, Fujii K.
    • Organizer
      Free Radical Biol Med
    • Place of Presentation
      St.Thomas, U.S.A.
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Presentation] Role of ethanol-induced NF-kappaB activation in the liver

    • Author(s)
      Matsumoto H.
    • Organizer
      ISBRA Satellite Symposium on Alcohol and the Liver : Nutritional and pathophysiological Aspects
    • Place of Presentation
      Bordeaux, France
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary

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Published: 2004-04-01   Modified: 2016-04-21  

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