Mechanisms of Mallory body formation and elimination in hepatocytes

• Project/Area Number: 20590798
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: University of Occupational and Environmental Health, Japan
• Principal Investigator: HARADA Masaru University of Occupational and Environmental Health, Japan, 医学部, 教授 (00241175)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2010: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2009: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2008: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 肝臓学 / Mallory-Denk体 / プロテアソーム / 小胞体ストレス / 酸化ストレス / オートファジー / ウイルス性肝炎 / ケラチン / 細胞内凝集体 / 蛋白分解

Research Abstract

Formation of Mallory-Denk bodies (MDB) was associated with abnormality of the intracellualr protein degradation system. Both proteasome and autophgy were associated with MDB formation. Endoplasmic reticulum stress and oxidative stress were related with MDB formation. MDB formation may be an adaptive response to these stresses. Modulation of autophagy was one of the therapeutic strategies of inclusion body-associated diseases including various liver diseases.

Research Products

• [Journal Article] Late diagnosed Wilson disease with hepatic and neurological manifestations. (2011)
  • Author(s): Honma Y, Harada M, Sato M, Katsuki Y, Hiura M, Shibata M, Narita R, Harada R, Abe S, Tabaru A, Tajiri N, Simajiri S
  • Journal Title: Hepatol Res 41 Pages: 270-276
  • Peer Reviewed
• [Journal Article] Late diagnosed Wilson disease with hepatic and neurological manifestations (2011)
  • Author(s): Yuichi Honma
  • Journal Title: Hepatol Res Volume: 41 Pages: 270-276
  • Peer Reviewed
• [Journal Article] Autophagy is involved in the elimination of intracellular inclusions, Mallory-Denk bodies, in hepatocytes. (2010)
  • Author(s): Harada M
  • Journal Title: Med Mol Morphol 43 Pages: 13-18
  • NAID: 10026443077
  • Peer Reviewed
• [Journal Article] 肝細胞Mallory-Denk体の細胞生物学的意義 (2010)
  • Author(s): 原田大
  • Journal Title: Medical Review 55 Pages: 268-269
• [Journal Article] Autophagy is involved in the elimination of intracellular inclusions, Mallory-Denk bodies, in hepatocytes (2010)
  • Author(s): Masaru Harada
  • Journal Title: Med Mol Morphol Volume: 43 Pages: 13-18
  • NAID: 10026443077
  • Peer Reviewed
• [Journal Article] Wilson disease and its current problems. (2010)
  • Author(s): Masaru Harada
  • Journal Title: Intern Med Volume: 49 Pages: 807-808
  • NAID: 130000251876
  • Peer Reviewed
• [Journal Article] Pigment epithelium-derived factor inhibits lysosomal degradation of Bc1-xL and apoptosis in HepG2 cells. (2010)
  • Author(s): Takumi Kawaguchi
  • Journal Title: Am J Pathol Volume: 176 Pages: 168-176
  • Peer Reviewed
• [Journal Article] Effect of long and short-term treatments with pravastatin on diabetes mellitus and pancreatic fibrosis in the Otsuka Long-Evans-Tokushima Fatty rat. (2010)
  • Author(s): Munenori Otani
  • Journal Title: Br J Pharmacol Volume: 159 Pages: 462-473
  • Peer Reviewed
• [Journal Article] Three cases of locally advanced pancreatic cancer successfully treated with chemoradiation and chemotherapy. (2010)
  • Author(s): Masashi Taguchi
  • Journal Title: Clin J Gastroenterol Volume: 3 Pages: 186-190
  • Peer Reviewed
• [Journal Article] A case of severe acute hepatitis C and delayed antibody production due to rituximab therapy. (2010)
  • Author(s): Masaaki Hiura
  • Journal Title: Clin J Gastroenterol Volume: 3 Pages: 254-258
  • Peer Reviewed
• [Journal Article] Acute hepatic failure secondary to extensive hepatic replacement by me tastatic amelanotic melanoma. (2010)
  • Author(s): Takayuki Fusasaki
  • Journal Title: Clin J Gastroenterol Volume: 3 Pages: 327-331
  • Peer Reviewed
• [Journal Article] Autophagy is involved in the elimination of intracellular inclusions, Mallory-Denk bodies, in hepatocytes (2010)
  • Author(s): Masaru Harada
  • Journal Title: Med Mol Morphol 43 Pages: 13-18
  • NAID: 10026443077
  • Peer Reviewed
• [Journal Article] Pigment epithelium-derived factor inhibits lysosomal degradation of Bcl-xL and apoptosis in HepG2 cells (2010)
  • Author(s): Takumi Kawaguchi
  • Journal Title: Am J Pathol 15 Pages: 168-176
  • Peer Reviewed
• [Journal Article] Niemann-Pick C1 protein transports copper to the secretory compartment from late endosomes where ATP7B resides (2009)
  • Author(s): Chikatoshi Yanagimoto
  • Journal Title: Exp Cell Res 15 Pages: 119-126
  • Peer Reviewed
• [Journal Article] Autophagy activfation by rapamycin eliminates mouse Mallory-Denk bodies and blocks their proteasome inhibitor-mediated formation. (2008)
  • Author(s): Harada M, Hanada S, Toivola DM, Ghori N, Omary MB
  • Journal Title: Hepatology 47 Pages: 2026-2035
  • Peer Reviewed
• [Journal Article] Autophagy modulates keratin-containing inclusion formation and apoptosis in cell culture in a context-dependent fashion. (2008)
  • Author(s): Harada M, Strnad P, Toivola DM, Omary MB
  • Journal Title: Exp Cell Res 314 Pages: 1753-1764
  • Peer Reviewed
• [Journal Article] Keratin mutation predisposes to mouse liver fibrosis and unmasks differential effects of the CCl4 and thioacetamide models. (2008)
  • Author(s): Strnad P, Tao GZ, Zhou Q, Harada M, Toivola DM, Brunt EM, Omary MB
  • Journal Title: Gastroenterology 134 Pages: 1169-1179
  • Peer Reviewed
• [Journal Article] Mutation in keratin 18 induces mitochondrial fragmentation in liver-derived epithelial cells. (2008)
  • Author(s): Kumemura H, Harada M, Yanagimoto C, Koga H, Kawaguchi T, Hanada S, Taniguchi E, Ueno T, Sata M
  • Journal Title: Biochem Biophys Res Commun 367 Pages: 33-40
  • Peer Reviewed
• [Journal Article] Autophagy modulates keratin-containing inclusion formation and apoptosis in cell culture in a context-dependent fashion. (2008)
  • Author(s): Masaru Harada, et al.
  • Journal Title: Experimental Cell Research 314 Pages: 1753-1764
  • Peer Reviewed
• [Journal Article] Autophagy activation by rapamyc in eliminates mouse Mallory-Denk bodies and blocks their proteasome inhibitor-mediated formation (2008)
  • Author(s): Masaru Harada, et al.
  • Journal Title: Hepatology 47 Pages: 2026-2035
  • Peer Reviewed
• [Journal Article] Mutation in keratin 18 induces mitochondrial fragmentation in liver-derived epithelial cells. (2008)
  • Author(s): Hiroto Kumemura, et al.
  • Journal Title: Biochemi cal and Biophysical Research Communication 367 Pages: 33-40
  • Peer Reviewed
• [Journal Article] Kerat in mutation predisposes to mouse liver fibrosis and unmasks differential effects of the CC14 and thioacetamide models. (2008)
  • Author(s): Strnad P, et al.
  • Journal Title: Gastroenterology 134 Pages: 1169-11179
  • Peer Reviewed
• [Journal Article] Excess copper chelating therapy for Wilson disease induces anemia and liver dysfunctions.
  • Author(s): Harada M, Miyagawa K, Honma Y, Hiura M, Shibata M, Matsuhashi T, Abe S, Harada R, Tabaru A
  • Journal Title: Intern Med (in press)
  • NAID: 130000969422
  • Peer Reviewed
• [Journal Article] Rapid progression of hepatocellular carcinoma in a patient with autoimmune hepatitis.
  • Author(s): Yamamoto K, Hiura M, Tabaru A, Honma Y, Narita R, Abe S, Shimajiri S, Okamoto K, Yamaguchi K, Harada M
  • Journal Title: Intern Med (in press)
  • NAID: 130000770517
  • Peer Reviewed
• [Journal Article] Copper incorporation into ceruloplasmin is regulated by Niemann-Pick C1 protein.
  • Author(s): Yanagimoto C, Harada M, Kumemura H, Abe M, Koga H, Sakata M, Kawaguchi T, Terada K, Hanada S, Taniguchi E, Ninomiya H, Ueno T, Sugiyama T, Sata M
  • Journal Title: Hepatol Res (in press)
  • NAID: 10031144114
  • Peer Reviewed
• [Presentation] DDC投与マウスモデルにおけるMallory-Denk body形成と性差 (2010)
  • Author(s): 花田慎一郎、原田大, 他
  • Organizer: 第30回アルコール医学生物学研究会
  • Place of Presentation: 久留米翠香園ホテル(久留米市)
  • Year and Date: 2010-11-26
• [Presentation] Proteasome inhibition induces Mallory-Denk body in susceptible mice and it is prevented by activation of autophagy. (2010)
  • Author(s): Harada M
  • Organizer: The 9th JSH single topic conference NASH 2010
  • Place of Presentation: 東京
  • Year and Date: 2010-11-19
• [Presentation] Proteasome inhibition induces Mallory-Denk body in susceptible mice and it is prevented by activation of autophagy (2010)
  • Author(s): Masaru Harada
  • Organizer: The 9^<th> JSH Single Topic Conference NASH 2010
  • Place of Presentation: Grand Prince Hotel Takanawa(Tokyo)
  • Year and Date: 2010-11-19
• [Presentation] DDC投与マウスモデルにおいて性差がMallory-Denk Body形成に与える影響について (2010)
  • Author(s): 花田慎一郎、原田大, Snider N., Brunt E., Hollenberg P.、佐田通夫、Omary, B
  • Organizer: 第14回日本肝臓学会大会
  • Place of Presentation: 横浜
  • Year and Date: 2010-10-14
• [Presentation] DDC投与マウスモデルにおいて性差がMallory-Denk body形成に与える影響について (2010)
  • Author(s): 花日慎一郎、原田大, 他
  • Organizer: 第14回日本肝臓学会大会
  • Place of Presentation: パシフィコ横浜(横浜市>
  • Year and Date: 2010-10-14
• [Presentation] DDC投与マウスモデルにおけるMallory-Denk Body形成と性差 (2010)
  • Author(s): 花田慎一郎、原田大、Snider N., Brunt E、鳥村拓司、上野隆登、佐田通夫、Omary B
  • Organizer: 第42回日本臨床分子形態学会総会・学術集会
  • Place of Presentation: 静岡
  • Year and Date: 2010-09-24
• [Presentation] 肝細胞内封入体Mallory-Denk体の細胞生物学的意義と分解機構 (2010)
  • Author(s): 原田大
  • Organizer: 第42回日本臨床分子形態学会総会・学術集会
  • Place of Presentation: 静岡
  • Year and Date: 2010-09-24
• [Presentation] 肝細胞内封入体Mallory-Denk体の細胞生物学的意義と分解機構 (2010)
  • Author(s): 原田大
  • Organizer: 第42回日本臨床分子形態学会総会
  • Place of Presentation: 東レ総合研修センター(静岡県)
  • Year and Date: 2010-09-24
• [Presentation] DDC投与マウスモデルにおけるMallory-Denk body形成と性差 (2010)
  • Author(s): 花日慎一郎、原田大, 他
  • Organizer: 第42回日本臨床分子形態学会総会
  • Place of Presentation: 東レ総合研修センター(静岡県)
  • Year and Date: 2010-09-24
• [Presentation] Phosphorylation of keratin 8 is important for Mallory Denk-body formation and protection of hepatocytes. (2010)
  • Author(s): Harada M
  • Organizer: Miami Clinical Exchange Program. Liver disease in Japan and USA
  • Place of Presentation: Miami
  • Year and Date: 2010-03-16
• [Presentation] Phosphorylation of keratin 8 is important for Mallory-Denk body formation and protection of hepatocytes (2010)
  • Author(s): Masaru Harada
  • Organizer: Liver diseasae in Japan and USA
  • Place of Presentation: University of Miami School of Medicine(Miami, USA)
  • Year and Date: 2010-03-16
• [Presentation] 肝細胞のMallory-Denk体形成におけるケラチン8リン酸化の意義 (2009)
  • Author(s): 原田大、本間雄一、佐藤みゆき、香月友香
  • Organizer: 第17回浜名湖シンポジウム
  • Place of Presentation: 浜松
  • Year and Date: 2009-12-22
• [Presentation] 肝細胞のMallory-Denk体形成におけるケラチン8リン酸化の意義 (2009)
  • Author(s): 原田大
  • Organizer: 第17回浜名湖シンポジウム
  • Place of Presentation: アクトシティ浜松コングレスセンター(浜松市)
  • Year and Date: 2009-12-22
• [Presentation] Mallory-Denk体の細胞生物学的意義 (2009)
  • Author(s): 原田大
  • Organizer: 第25回九州肝臓談話会
  • Place of Presentation: 熊本
  • Year and Date: 2009-09-05
• [Presentation] Mallory-Denk体の細胞生物学的意義 (2009)
  • Author(s): 原田大
  • Organizer: 第25回九州肝臓談話会
  • Place of Presentation: ホテル グリーンピア南阿蘇(熊本県)
  • Year and Date: 2009-09-05
• [Presentation] 肝細胞でのMallory-Denk body形成におけるケラチン8ならびにそのリン酸化の役割 (2009)
  • Author(s): 原田大
  • Organizer: 第45回日本肝臓学会総会
  • Place of Presentation: 神戸
  • Year and Date: 2009-06-04
• [Presentation] 肝細胞でのMallory-Denk body形成におけるケラチン8ならびにそのリン酸化の役割 (2009)
  • Author(s): 原田大
  • Organizer: 第45回日本肝臓学会総会
  • Place of Presentation: 神戸ポートピアホテル・神戸国際展示場(神戸市)
  • Year and Date: 2009-06-04
• [Presentation] 封入体関連疾患のオートファジー調節による新しい治療戦略 (2009)
  • Author(s): 原田大、佐田通夫
  • Organizer: 第1回福岡県医学会総会
  • Place of Presentation: 福岡
  • Year and Date: 2009-01-25
• [Presentation] プロテアソームの機能障害によるMallory-Denk体の形成をオートファジーは抑制する (2008)
  • Author(s): 原田大、佐田通夫
  • Organizer: 第16回浜名湖シンポジウム
  • Place of Presentation: 静岡
  • Year and Date: 2008-12-21
• [Presentation] Autophagy is involved in elimination of components of Mallory-Denk bodies in two different types of mouse models. (2008)
  • Author(s): Harada M, Sata M
  • Organizer: The 59^<th> Annual Meeting of the American Association for the Study of Liver Diseases.
  • Place of Presentation: San Francisco
  • Year and Date: 2008-11-01
• [Presentation] オートファジーはプロテアソームの機能異常によるMallory-Denk体の形成を抑制する (2008)
  • Author(s): 原田大
  • Organizer: 第40回日本臨床分子形態学会
  • Place of Presentation: 福岡
  • Year and Date: 2008-10-03
• [Presentation] オートファジーはプロテアソームの機能異常によるMallory-Denk体の形成を抑制する。 (2008)
  • Author(s): 原田大
  • Organizer: 第40回日本臨床分子形態学会
  • Place of Presentation: 福岡
  • Year and Date: 2008-10-03
• [Presentation] Mallory-Denk体形成におけるプロテアソーム、オートファジーの関与 (2008)
  • Author(s): 原田大
  • Organizer: 第44回日本肝臓学会総会
  • Place of Presentation: 松山
  • Year and Date: 2008-06-05
• [Presentation] Mallory-Denk体形成におけるプロテアソーム、オートファジーの役割。 (2008)
  • Author(s): 原田大
  • Organizer: 第44回日本肝臓学会総会
  • Place of Presentation: 松山
• [Presentation] プロテアソームの機能障害によるMallory-Denk体形成をオートファジーは抑制する。 (2008)
  • Author(s): 原田大
  • Organizer: 第16回浜名湖シンポジウム
  • Place of Presentation: 浜松
• [Book] 日本メディカルセンター肝疾患Review 2010-2011 (2010)
  • Author(s): 原田大、本間雄一、日浦政明
• [Book] アークメディア分子標的薬 (2010)
  • Author(s): 原田大、本間雄一、佐藤みゆき、香月友香
• [Book] 肝・胆道系症候群 (2010)
  • Author(s): 原田大
  • Total Pages: 3
  • Publisher: 日本臨床社
• [Book] 肝疾患Review 2010-2011 (2010)
  • Author(s): 原田大
  • Total Pages: 4
  • Publisher: 日本メディカルセンター
• [Book] 遺伝性肝疾患 (2010)
  • Author(s): 原田大
  • Total Pages: 4
  • Publisher: 中外医学社
• [Book] 分子標的薬 (2010)
  • Author(s): 原田大
  • Total Pages: 2
  • Publisher: アークメディア
• [Book] アークメディア消化器疾患におけるエピゲノミクスとゲノミクス (2009)
  • Author(s): 原田大
• [Book] 消化器疾患にかけるエピゲノイクスとゲノミクス (2009)
  • Author(s): 原田大
  • Total Pages: 5
  • Publisher: アークメディア
• [Remarks] ホームページ等