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Role of Kupffer cells on chronic liver injury

Research Project

Project/Area Number 21790657
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeSingle-year Grants
Research Field Gastroenterology
Research InstitutionGifu University

Principal Investigator

OSAWA Yosuke  Gifu University, 医学系研究科, 助教 (60447787)

Project Period (FY) 2009 – 2010
Project Status Completed (Fiscal Year 2010)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2010: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2009: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Keywords慢性肝障害 / アポトーシス / クッパー細胞 / 肝細胞 / スフィンゴ脂質 / 糖代謝 / 脂質代謝 / 肝再生 / 肝線維化 / 脂肪肝
Research Abstract

Background and Aims : Kupffer cells, resident tissue macrophages of the liver, play a key role in the regulation of hepatic inflammation, hepatocyte death, and fibrosis that characterize liver diseases. However, it is controversial whether Kupffer cell promotes or protects from liver injury. To explore this issue, we examined the role of Kupffer cell in liver injury, cell death, regeneration, and fibrosis on cholestatic liver injury. Methods : A model of partial bile duct ligation (PBDL) was developed. The left hepatic duct of wild-type C57BL/6 male mice was ligated with 6-0 silk, and the animals were sacrificed 10 days after the surgery. Liver injury, regeneration, and fibrosis were compared between the ligated left and non-ligated right lobes. Hepatocyte apoptosis was induced by administration of D-galactosamine and TNF-alpha to the PBDL mice. The effects of Kupffer cell depletion by alendronate liposomes, or inhibition of AKT by adenovirus expressing dominant-negative AKT were investigated. Results : In the cholestatic liver injury, remaining viable cells represented tolerance for tumor necrosis factor (TNF)-α-induced hepatocyte apoptosis and regenerative features along with AKT activation. Inhibition of AKT abolished the survival and regenerative properties in hepatocytes. Moreover, Kupffer cell depletion increased hepatocyte damage and the sensitivity of TNF-α-induced hepatocyte apoptosis in ligated lobes. Kupffer cell depletion decreased hepatocyte regeneration and liver fibrosis with reduced AKT activation. Conclusion: Kupffer cell has a protective role for hepatocyte damage, and promotes cell survival, liver regeneration, and fibrosis in cholestatic liver disease. Kupffer cell is crucial for AKT activation of hepatocytes that is required for the survival and regenerative responses.

Report

(3 results)
  • 2010 Annual Research Report   Final Research Report ( PDF )
  • 2009 Annual Research Report
  • Research Products

    (47 results)

All 2011 2010 2009 Other

All Journal Article (22 results) (of which Peer Reviewed: 22 results) Presentation (24 results) Book (1 results)

  • [Journal Article] Imaging the recruitment of cancer-associated fibroblasts by liver-metastatic colon cancer.2011

    • Author(s)
      Suetsugu, A., Osawa, Y., Nagaki, M., Saji, S., Moriwaki, H., Bouvet, M., Hoffman, R.M.
    • Journal Title

      J Cell Biochem. 112

      Pages: 949-953

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Acid sphingomyelinase regulates glucose and lipid metabolism in hepatocytes through AKT activation and AMP-activated protein kinase suppression.2011

    • Author(s)
      Osawa Y, ら
    • Journal Title

      FASEB J.

      Volume: 25 Pages: 1133-1144

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Imaging the recruitment of cancer-associated fibroblasts by liver-metastatic colon cancer.2011

    • Author(s)
      Suetsugu A, Osawa Y, ら
    • Journal Title

      J Cell Biochem.

      Volume: 112 Pages: 949-953

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Ability of IDO to attenuate liver injury in alpha-galactosylceramide-induced hepatitis model.2010

    • Author(s)
      Ito, H., Hoshi, M., Ohtaki, H., Taguchi, A., Ando, K., Ishikawa, T., Osawa, Y., Hara, A., Moriwaki, H., Saito, K., Seishima, M.
    • Journal Title

      J Immunol. 185

      Pages: 4554-4550

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] The absence of IDO upregulates type I IFN production, resulting in suppression of viral replication in the retrovirus-infected mouse.2010

    • Author(s)
      Hoshi, M., Saito, K., Hara, A., Taguchi, A., Ohtaki, H., Tanaka, R., Fujigaki, H., Osawa, Y., Takemura, M., Matsunami, H., Ito, H., Seishima, M.
    • Journal Title

      J Immunol. 185

      Pages: 3305-3312

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Simultaneous color-coded imaging to distinguish cancer "stem-like" and non-stem cells in the same tumor.2010

    • Author(s)
      Suetsugu, A., Osawa, Y., Nagaki, M., Moriwaki, H., Saji, S., Bouvet, M., Hoffman, R.M.
    • Journal Title

      J Cell Biochem. 111

      Pages: 1035-1041

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Role of acid sphingomyelinase of Kupffer cells in cholestatic liver injury in mice.2010

    • Author(s)
      Osawa, Y., Seki, E., Adachi, M., Suetsugu, A., Ito, H., Moriwaki, H., Seishima, M., Nagaki, M.
    • Journal Title

      Hepatology. 51

      Pages: 237-245

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Ability of IDO to attenuate liver injury in alpha-galactosylcer amide-induced hepatitis model.2010

    • Author(s)
      Ito H, Osawa Y, ら
    • Journal Title

      J Immunol.

      Volume: 185 Pages: 4554-4550

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The absence of IDO upregulates type I IFN production, resulting in suppression of viral replication in the retrovirus-infected mouse.2010

    • Author(s)
      Hoshi M, Osawa Y, ら
    • Journal Title

      J Immunol.

      Volume: 185 Pages: 3305-3312

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Simultaneous color-coded imaging to distinguish cancer "stem-like" and non-stem cells in the same tumor.2010

    • Author(s)
      Suetsugu A, Osawa Y, ら
    • Journal Title

      J Cell Biochem.

      Volume: 111 Pages: 1035-1041

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Role of acid sphingomyelinase of Kupffer cells in cholestatic liver injury in mice.2010

    • Author(s)
      Osawa Y, ら
    • Journal Title

      Hepatology 51

      Pages: 237-245

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] (-)-Epigallocatechin gallate prevents carbon tetrachloride-induced rat hepatic fibrosis by inhibiting the expression of the PDGFRbeta and IGF-1R.2009

    • Author(s)
      Yasuda, Y., Shimizu, M., Sakai, H., Iwasa, J., Kubota, M., Adachi, S., Osawa, Y., Tsurumi, H., Hara, Y., Moriwaki, H.
    • Journal Title

      Chem Biol Interact. 182

      Pages: 159-164

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Interaction between LPS-induced NO production and IDO activity in mouse peritoneal cells in the presence of activated Valpha14 NKT cells.2009

    • Author(s)
      Ohtaki, H., Ito, H., Ando, K., Ishikawa, T., Hoshi, M., Tanaka, R., Osawa, Y., Yokochi, T., Moriwaki, H., Saito, K., Seishima, M.
    • Journal Title

      Biochem Biophys Res Commun. 389

      Pages: 229-234

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Extracellular matrix is required for the survival and differentiation of transplanted hepatic progenitor cells.2009

    • Author(s)
      Tsukada, Y., Nagaki, M., Suetsugu, A., Osawa, Y., Moriwaki, H.
    • Journal Title

      Biochem Biophys Res Commun 381

      Pages: 733-737

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Sphingosine kinase isoforms regulate oxaliplatin sensitivity of human colon cancer cells through ceramide accumulation and AKT activtion.2009

    • Author(s)
      Nemoto, S., Nakamura, M., Osawa, Y., Kono, S., Itoh, Y., Okano, Y., Murate, T., Hara, A., Ueda, H., Nozawa, Y., Banno, Y.
    • Journal Title

      J Biol Chem (in print)

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Antiapoptotic effect of c-Jun N-terminal Kinase-1 through Mcl-1 stabilization in TNF-induced hepatocyte apoptosis.2009

    • Author(s)
      Kodama, Y., Taura, K., Miura, K., Schnabl, B., Osawa, Y., Brenner, D.A.
    • Journal Title

      Gastroenterology 136

      Pages: 1423-1434

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Interaction between LPS-induced NO production and IDO activity in mouse peritoneal cells in the presence of activated Valphal4 NKT cells.2009

    • Author(s)
      Ohtaki H, Osawa Y, ら
    • Journal Title

      Biochem Biophys Res Commun. 389

      Pages: 229-234

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] (-)-Epigallocatechin gallate prevents carbon tetrachloride-induced rat hepatic fibrosis by inhibiting the expression of the PDGFRbeta and IGF-1R.2009

    • Author(s)
      Yasuda Y, Osawa Y, ら
    • Journal Title

      Chem Biol Interact. 182

      Pages: 159-164

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Extracellular matrix is required for the survival and differentiation of transplanted hepatic progenitor cells.2009

    • Author(s)
      Tsukada Y, Osawa Y, ら
    • Journal Title

      Biochem Biophys Res Commun. 381

      Pages: 733-737

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Antiapoptotic effect of c-Jun N-terminal Kinase-1 through Mcl-1 stabilization in TNF-induced hepatocvte apoptosis.2009

    • Author(s)
      Kodama Y, Osawa Y, ら
    • Journal Title

      Gastroenterology. 136

      Pages: 1423-1434

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Sphingosine kinase isoforms regulate oxaliplatin sensitivity of human colon cancer cells through ceramide accumulation and Akt activation.2009

    • Author(s)
      Nemoto S, Osawa Y, ら
    • Journal Title

      J Biol Chem. 284

      Pages: 10422-10432

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Acid sphingomyelinase regulates glucose and lipid metabolism in hepatocytes through AKT activation and AMP-activated protein kinase suppression.

    • Author(s)
      Osawa, Y., Seki, E., Kodama, Y., Suetsugu, A., Miura.K., Adachi, M., Ito, H., Shirator,i Y., Banno, Y., Olefsky, J.M., Nagaki, M., Moriwaki, H., Brenner, D.A., Seishima, M.
    • Journal Title

      FASEB J. in press.

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Presentation] Roles of acid sphingomyelinase on glucose and lipid metabolism in hepatocytes.2011

    • Author(s)
      Osawa Y, ら
    • Organizer
      Asian Pacific Association for the Study of the Liver 2011
    • Place of Presentation
      タイバンコク
    • Year and Date
      2011-02-19
    • Related Report
      2010 Annual Research Report
  • [Presentation] A lipophilic statin, pitavastatin, suppresses azoxymethane-induced and obesity-related colonic premalignant lesions in male db/db mice.2011

    • Author(s)
      Yasuda Y, Osawa Y, ら
    • Organizer
      Asian Pacific Association for the Study of the Liver 2011
    • Place of Presentation
      タイバンコク
    • Year and Date
      2011-02-19
    • Related Report
      2010 Annual Research Report
  • [Presentation] Roles of acid sphingomyelinase on glucose and lipid metabolism in hepatocytes.2011

    • Author(s)
      Osawa Y, Nagaki M, Yasuda Y, Moriwaki H, Seishima M
    • Organizer
      Asian Pacific Association for the Study of the Liver (APASL) 2011.
    • Place of Presentation
      Bangkok.Thailand
    • Related Report
      2010 Final Research Report
  • [Presentation] A lipophilic statin, pitavastatin, suppresses azoxymethane-induced and obesity-related colonic premalignant lesions in male db/db mice.2011

    • Author(s)
      Yasuda Y, Shimizu M, Sakai H, Kubota M, Osawa Y, Moriwaki H
    • Organizer
      Asian Pacific Association for the Study of the Liver (APASL) 2011.
    • Place of Presentation
      Bangkok.Thailand
    • Related Report
      2010 Final Research Report
  • [Presentation] Inhibition of acid sphingomyelinase causes hepatic glucose intolerance and insulin resistance.2010

    • Author(s)
      Osawa Y, ら
    • Organizer
      Digestive Disease Week (DDW) 2010
    • Place of Presentation
      米国ニューオリンズ
    • Year and Date
      2010-05-03
    • Related Report
      2010 Annual Research Report
  • [Presentation] An analysis of CD133 positive bone marrow in oval cell induced model and a role of CD133 bone marrow in mice with liver fibrosis.2010

    • Author(s)
      Suetsugu A, Osawa Y, ら
    • Organizer
      Digestive Disease Week (DDW) 2010
    • Place of Presentation
      米国ニューオリンズ
    • Year and Date
      2010-05-03
    • Related Report
      2010 Annual Research Report
  • [Presentation] Role of Kupffer cells in cholestatic liver injury in mice.2010

    • Author(s)
      Osawa Y, ら
    • Organizer
      Asian Pacific Association for the Study of the Liver (APASL) 2010
    • Place of Presentation
      中国北京
    • Year and Date
      2010-03-25
    • Related Report
      2009 Annual Research Report
  • [Presentation] Extracellular matrix is required for the survival and differentiation of transplanted hepatic progenitor cells.2010

    • Author(s)
      Tsukada Y, Osawa Y, ら
    • Organizer
      Asian Pacific Association for the Study of the Liver (APASL) 2010
    • Place of Presentation
      中国北京
    • Year and Date
      2010-03-25
    • Related Report
      2009 Annual Research Report
  • [Presentation] (-)-Epigallocatechin gallate prevents carbon tetrachloride-induced rat hepatic fibrosis by inhibiting the expression of the PDGFR and IGF-1R.2010

    • Author(s)
      Yasuda Y, Osawa Y, ら
    • Organizer
      Asian Pacific Association for the Study of the Liver (APASL) 2010
    • Place of Presentation
      中国北京
    • Year and Date
      2010-03-25
    • Related Report
      2009 Annual Research Report
  • [Presentation] Color-coded imaging of tumor growth, metastasis and drug resistance of co-implanted cancer stem cells and non-cancer stem cells.2010

    • Author(s)
      Suetsugu A, Osawa Y, Nagaki M, Moriwaki H, Bouvet M, Hoffman RM
    • Organizer
      American association of cancer research 101^<st> annual meeting 2010.
    • Place of Presentation
      Washington DC USA
    • Related Report
      2010 Final Research Report
  • [Presentation] Use of RFP and GFP transgenic nude mice to study the tumor microenvironment of metastasis.2010

    • Author(s)
      Suetsugu A, Osawa Y, Nagaki M, Saji S, Moriwaki H, Momiyana M, Bouvet M, Hoffman RM
    • Organizer
      American association of cancer research 101^<st> annual meeting 2010.
    • Place of Presentation
      Washington DC USA
    • Related Report
      2010 Final Research Report
  • [Presentation] Inhibition of acid sphingomyelinase causes hepatic glucose intolerance and insulin resistance.2010

    • Author(s)
      Osawa Y, Ito H, Suetsugu A, Nagaki M, Moriwaki H, Seishima M
    • Organizer
      Digestive Disease Week (DDW) 2010.
    • Place of Presentation
      New Orleans USA
    • Related Report
      2010 Final Research Report
  • [Presentation] An analysis of CD133 positive bone marrow in oval cell induced model and a role of CD133 bone marrow in mice with liver fibrosis.2010

    • Author(s)
      Suetsugu A, Nagaki M, Osawa Y, Hoffman RM, Moriwaki H
    • Organizer
      Digestive Disease Week (DDW) 2010.
    • Place of Presentation
      New Orleans USA
    • Related Report
      2010 Final Research Report
  • [Presentation] Role of Kupffer cells in cholestatic liver injury in mice.2010

    • Author(s)
      Osawa Y, Nagaki M, Yasuda Y, Tsukada Y, Moriwaki H, Seishima M
    • Organizer
      Asian Pacific Association for the Study of the Liver (APASL) 2010.
    • Place of Presentation
      Beijin.China
    • Related Report
      2010 Final Research Report
  • [Presentation] Extracellular matrix is required for the survival and differentiation of transplanted hepatic progenitor cells.2010

    • Author(s)
      Tsukada Y, Nagaki M, Suetsugu A, Osawa Y, Moriwaki H
    • Organizer
      Asian Pacific Association for the Study of the Liver (APASL) 2010.
    • Place of Presentation
      Beijing.China
    • Related Report
      2010 Final Research Report
  • [Presentation] (-)-Epigallocatechin gallate prevents carbon tetrachloride-induced rat hepatic fibrosis by inhibiting the expression of the PDGFR and IGF-1R.2010

    • Author(s)
      Yasuda Y, Shimizu M, Sakai H, Kubota M, Osawa Y, Hara Y, Moriwaki H
    • Organizer
      Asian Pacific Association for the Study of the Liver (APASL) 2010.
    • Place of Presentation
      Beijing.China
    • Related Report
      2010 Final Research Report
  • [Presentation] パネルディスカッション「肝臓の再生機構を考える:今後の肝再生医療への展望」肝細胞死と肝再生・肝線維化連携機構におけるKupffer細胞の役割2010

    • Author(s)
      大澤陽介, 永木正仁, 森脇久隆
    • Organizer
      第14回日本肝臓学会大会
    • Place of Presentation
      横浜
    • Related Report
      2010 Annual Research Report 2010 Final Research Report
  • [Presentation] 胆管結紮誘導性慢性肝障害マウスモデルにおけるKupffer細胞の役割2009

    • Author(s)
      大澤陽介, ら
    • Organizer
      第13回日本肝臓学会大会
    • Place of Presentation
      京都
    • Year and Date
      2009-10-14
    • Related Report
      2009 Annual Research Report
  • [Presentation] TLR4-MyD88-NFκBシグナルによる肝星細胞活性化と肝線維症における役割2009

    • Author(s)
      石亦宏、大澤陽介, ら
    • Organizer
      第13回日本肝臓学会大会
    • Place of Presentation
      京都
    • Year and Date
      2009-10-14
    • Related Report
      2009 Annual Research Report
  • [Presentation] 胆管結紮誘導性慢性肝障害モデルにおける肝細胞抗アポトーシス獲得機序の検討2009

    • Author(s)
      大澤陽介, ら
    • Organizer
      第45回日本肝臓学会総会
    • Place of Presentation
      神戸
    • Year and Date
      2009-06-04
    • Related Report
      2009 Annual Research Report
  • [Presentation] Anti-apoptotic effects against TNF-alpha treatment in bile duct ligated mouse liver2009

    • Author(s)
      Osawa Y, ら
    • Organizer
      Digestive Disease Week (DDW) 2009
    • Place of Presentation
      米国シカゴ
    • Year and Date
      2009-05-31
    • Related Report
      2009 Annual Research Report
  • [Presentation] Anti-apoptotic effects against TNF-alpha treatment in bile duct ligated mouse liver.2009

    • Author(s)
      Osawa Y, Nagaki M, Ito H, Seishima M, Moriwaki H
    • Organizer
      Digestive Disease Week (DDW) 2009.
    • Place of Presentation
      Chicago USA
    • Related Report
      2010 Final Research Report
  • [Presentation] ワークショップ「免疫担当細胞異常からみた肝疾患の動態」胆管結紮誘導性慢性肝障害マウスモデルにおけるKupffer細胞の役割2009

    • Author(s)
      大澤陽介, 永木正仁, 森脇久隆
    • Organizer
      第13回日本肝臓学会大会
    • Place of Presentation
      京都
    • Related Report
      2010 Final Research Report
  • [Presentation] パネルディスカッション「自然免疫と消化器疾患」TLR4-MyD88-NFκBシグナルによる肝 星細胞活性化と肝線維症における役割2009

    • Author(s)
      石亦宏, 大澤陽介, 藤本治朗
    • Organizer
      第13回日本肝臓学会大会
    • Place of Presentation
      京都
    • Related Report
      2010 Final Research Report
  • [Book] 2nd edition of Essentials of Apoptosis. Part III Apoptosis in mammalian physiology and pathogenesis. Chapter 24 Apoptosis in liver injury and liver diseases.2009

    • Author(s)
      Osawa, Y., Seki, E., Brenner DA.
    • Publisher
      Springer
    • Related Report
      2010 Final Research Report

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Published: 2009-04-01   Modified: 2016-04-21  

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