Bcl-2 network and regulation of cell death in non-alcoholic steatohepatitis

• Project/Area Number: 21659188
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Gastroenterology
• Research Institution: Osaka University
• Principal Investigator: TAKEHARA Tetsuo 大阪大学, 大学院・医学系研究科, 教授 (70335355)
• Co-Investigator(Kenkyū-buntansha): TATSUMI Tomohide 大阪大学, 医学系・研究科, 助教 (20397699)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥3,300,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥300,000); Fiscal Year 2011: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2010: ¥1,000,000 (Direct Cost: ¥1,000,000); Fiscal Year 2009: ¥1,000,000 (Direct Cost: ¥1,000,000)
• Keywords: アポトーシス / Bcl-2 / 肝細胞 / Bcl-xL / Mcl-1 / Bak / NASH / ノックアウトマウス / 肝線維化 / 肝癌 / Bid / apoptosis / ノックアウト / Cre

Research Abstract

Apoptosis is a characteristic feature for hepatocyte cell death in non-alcoholic steatohepatitis. The aim of this study is to examine the significance and regulation of hepatocyte apoptosis, using several kinds of knockout mice targeting the Bcl-2 family genes. The study revealed that hepatocyte apoptosis is regulated by a fine balance between anti-apoptotic and pro-apoptotic Bcl-2 family and that excessive apoptosis is directly linked to hepatocarcinogenesis.

Research Products

• [Journal Article] Bak deficiency inhibits liver carcinogenesis : A causal link between apoptosis and carcinogenesi (2012)
  • Author(s): Hikita H, Kodama T, Shimizu S, Li W, Shigekawa M, Tanaka S, Hosui A, Miyagi T, Tatsumi T, Kanto T, Hiramatsu N, Morii E, Hayashi N, Takehara T
  • Journal Title: J Hepatol Volume: (in press)
  • Peer Reviewed
• [Journal Article] Inhibition of autophagy potentiates the antitumor effect of the multikinase inhibitor sorafenib in hepatocellular carcinoma (2012)
  • Author(s): Shimizu S, Takehara T, Hikita H, Kodama T, Tsunematsu H, Miyagi T, Hosui A, Ishida H, Tatsumi T, Kanto T, Hiramatsu N, Fujita N, Yoshimori T, Hayashi N
  • Journal Title: Int J Cancer Volume: (in press)
  • Peer Reviewed
• [Journal Article] Bak deficiency inhibits liver carcinogenesis : A causal link between apoptosis and carcinogenesis (2012)
  • Author(s): Hikita H, Takehara T, et al
  • Journal Title: Journal of Hepatology Volume: (印刷中) Issue: 1 Pages: 92-100
  • DOI: 10.1016/j.jhep.2012.01.027
  • Peer Reviewed
• [Journal Article] Increases in p53 expression induce CTGF synthesis by mouse and human hepatocytes and result in liver fibrosis in mice (2011)
  • Author(s): Kodama T, Takehara T, Hikita H, Shimizu S, Shigekawa M, Tsunematsu H, Li W, Miyagi T, Hosui A, Tatsumi T, Ishida H, Kanto T, Hiramatsu N, Kubota S, Takigawa M, Tomimaru Y, Tomokuni A, Nagano H, Doki Y, Mori M, Hayashi N
  • Journal Title: J Clin Invest Volume: 121 Pages: 3343-3356
  • Peer Reviewed
• [Journal Article] Delayed-onset caspase-dependent massive hepatocyte apoptosis upon Fas activation in Bak/ Bax-deficient mice (2011)
  • Author(s): Hikita H, Takehara T, Kodama T, Shimizu S, Shigekawa M, Hosui A, Miyagi T, Tatsumi T, Ishida H, Li W, Kanto T, Hiramatsu N, Shimizu S, Tsujimoto Y, Hayashi N
  • Journal Title: Hepatology Volume: 54 Pages: 240-251
  • Peer Reviewed
• [Journal Article] BH3-only activator proteins, Bid and Bim, are dispensable for Bak/ Bax-dependent thrombocyte apoptosis induced by Bcl-xL deficiency : Molecular requisites for the mitochondrial pathway to apoptosis in platelets (2011)
  • Author(s): Kodama T, Takehara T, Hikita H, Shimizu S, Shigekawa M, Li W, Miyagi T, Hosui A, Tatsumi T, Ishida H, Kanto T, Hiramatsu N, Yin XM, Hayashi N
  • Journal Title: J Biol Chem Volume: 286 Pages: 13905-13913
  • Peer Reviewed
• [Journal Article] Delayed-onset caspase-dependent massive hepatocyte apoptosis upon Fasactivation in Bak/Bax-deficient mice (2011)
  • Author(s): Hikita, H.
  • Journal Title: Hepatology Volume: VOL. 54 Issue: 1 Pages: 240-251
  • DOI: 10.1002/hep.24305
  • Peer Reviewed
• [Journal Article] The Bcl-xL inhibitor, ABT-737, efficiently induces apoptosis and suppresses growth of hepatoma cells in combination with sorafenib (2010)
  • Author(s): Hikita H, Takehara T, Shimizu S, Kodama T, Shigekawa M, Iwase K, Hosui A, Miyagi T, Tatsumi T, Ishida H, Li W, Kanto T, Hiramatsu N, Hayashi N
  • Journal Title: Hepatology Volume: 52 Pages: 1310-1321
  • NAID: 40018998703
  • Peer Reviewed
• [Journal Article] Thrombocytopenia exacerbates cholestasis-induced liver fibrosis in mice (2010)
  • Author(s): Kodama T, Takehara T, Hikita H, Shimizu S, Wei Li, Miyagi T, Hosui A, Tatsumi T, Ishida H, Tadokoro S, Ido A, Tsubouchi H, Hayashi N
  • Journal Title: Gastroenterology Volume: 138 Pages: 2487-2498
  • NAID: 40017376760
  • Peer Reviewed
• [Journal Article] Lack of invariant natural killer cells elicits liver inflammation and predispores to liver fibrosis in mice fed with high-fat-diet. (2010)
  • Author(s): Miyagi T, Takehara T, et al.
  • Journal Title: J Gastroenterol Volume: 45 Pages: 1247-1254
  • Peer Reviewed
• [Journal Article] The Bcl-xL inhibitor, ABT-737, efficiently induces apoptosis and suppresses growth of hepatoma cells in combination with sorafenib. (2010)
  • Author(s): Hikita H, Takehara T, et al.
  • Journal Title: Hepatology Volume: 52 Pages: 1310-1321
  • NAID: 40018998703
  • Peer Reviewed
• [Journal Article] The let-7 family of microRNAs negatively regulates Bcl-xL expression and potentiates sorafenib-induced apoptosis in human hepatocellular carcinoma. (2010)
  • Author(s): Shimizu S, Takehara T, et al.
  • Journal Title: J Hepatol Volume: 52 Pages: 698-704
  • Peer Reviewed
• [Journal Article] BH3-only protein Bid participates in the Bcl-2 network in healthy liver cells. (2010)
  • Author(s): Hikita H, Takehara T, et al.
  • Journal Title: Hepatology 50 Pages: 1972-1980
  • Peer Reviewed
• [Journal Article] BH3-only protein Bid participates in the Bcl-2 network in healthy liver cells (2009)
  • Author(s): Hikita H, Takehara T, Kodama T, Shimizu S, Hosui A, Miyagi T, Tatsumi T, Ishida H, Ohkawa K, Li W, Kanto T, Hiramatsu N, Hennighausen L, Yin XM, Hayashi N
  • Journal Title: Hepatology Volume: 50 Pages: 1972-1980
  • Peer Reviewed
• [Journal Article] Mcl-1 and Bcl-xL cooperatively maintain integrity of hepatocytes in developing and adult murine liver (2009)
  • Author(s): Hikita H, Takehara T, Shimizu S, Kodama T, Li W, Miyagi T, Hosui A, Ishida H, Ohkawa K, Kanto T, Hiramatsu N, Yin XM, Hennighausen L, Tatsumi T, Hayashi N
  • Journal Title: Hepatology Volume: 50 Pages: 1217-1226
  • Peer Reviewed
• [Journal Article] Mcl-1 and Bcl-xL cooperatively maintain integrity of hepatocytes in developing and adult murine liver. (2009)
  • Author(s): Hikita H, Takehara T, et al.
  • Journal Title: Hepatology 50 Pages: 1217-1226
  • Peer Reviewed
• [Presentation] Continuous hepatocyte apoptosis is sufficient for liver cancer development (2011)
  • Author(s): Hikita H, Takehara T, et al
  • Organizer: The American Association for the Study of Liver Diseases (AASLD), 62nd Annual Meeting
  • Place of Presentation: San Francisco, USA
  • Year and Date: 2011-11-07
• [Presentation] Requirement of BH3-only activator proteins Bid and Bim for apoptosis by genetic ablation of Bcl-xL is completely different between hepatocytes and platelets (2011)
  • Author(s): Takahiro Kodama, Hayato Hikita, Tsukasa Kawaguchi, Minoru Shigekawa, Hinako Tsunematsu, Kumiko Nishio, Takatoshi Nawa, Satoshi Shimizu, Takuya Miyagi, Atsushi Hosui, Tomohide Tatsumi, Hisashi Ishida, Tatsuya Kanto, Naoki Hiramatsu, Tetsuo Takehara
  • Organizer: The 62nd Annual Meeting of the American Association for the study of Liver Disease
  • Place of Presentation: San Francisco, USA
• [Presentation] Continuous hepatocyte apoptosis is sufficient for liver cancer development (2011)
  • Author(s): Hayato Hikita, Takahiro Kodama, Satoshi Shimizu, Minoru Shigekawa, Wei Li, Satoshi Tanaka, Atsushi Hosui, Takuya Miyagi, Hisashi Ishida, Tomohide Tatsumi, Tatsuya Kanto, Naoki Hiramatsu, Norio Hayashi, Tetsuo Takehara
  • Organizer: The 62nd Annual Meeting of the American Association for the study of Liver Disease
  • Place of Presentation: San Francisco, USA
• [Presentation] A crucial role of hepatocyte p53 in liver fibrogenesis (2011)
  • Author(s): Takahiro Kodama, Tetsuo Takehara, Satoshi Shimizu, Hayato Hikita, Minoru Shigekawa, Hinako Tsunematsu, Takuya Miyagi, Atsushi Hosui, Tomohide Tatsumi, Hisashi Ishida, Tatsuya Kanto, Naoki Hiramatsu, Norio Hayashi
  • Organizer: Digestive Disease Week 2011
  • Place of Presentation: Chicago, USA
• [Presentation] Delayed onset of caspase-dependent liver failure induced by Fas stimulation in Bak and Bax double knockout mice (2011)
  • Author(s): Hayato Hikita, Takahiro Kodama, Satoshi Shimizu, Minoru Shigekawa, Atsushi Hosui, Takuya Miyagi, Hisashi Ishida, Tomohide Tatsumi, Tatsuya Kanto, Naoki Hiramatsu, Norio Hayashi, Tetsuo Takehara
  • Organizer: Digestive Disease Week 2011
  • Place of Presentation: Chicago, USA
• [Presentation] ABT-737, a Bad mimetic Bcl-xL inhibitor, enhances the anti-tumor effect of sorafenib against hepatocellular carcinoma (2010)
  • Author(s): H. Hikita ; T. Takehara ; S. Shimizu ; T. Kodama ; W. Li ; M. Shigekawa ; A. Hosui ; T. Miyagi ; H. Ishida ; T. Tatsumi ; T. Kanto ; N. Hiramatsu ; N. Hayashi
  • Organizer: The 61st Annual Meeting of the American Association for the study of Liver Disease
  • Place of Presentation: Boston, USA
• [Presentation] ABT-737, a Bad mimetic Bcl-xL inhibitor, enhances the anti-tumor effect of sorafenib against hepatocellular carcinoma. (2010)
  • Author(s): Hikita H, Takehara T, et al.
  • Organizer: The Liver Meeting 2010
  • Place of Presentation: Boston, MA, USA
• [Presentation] Thrombocytopenia deteriorates cholestasis-induced liver fibrosis in mice (2009)
  • Author(s): Kodama T, Takehara T, Hikita H, Shimizu S, Li W, Miyagi T, Hosui A, Tatsumi T, Ishida H, Tadokoro S, Ido A, Tsubouchi H, Hayashi N
  • Organizer: The 60th Annual Meeting of the American Association for the study of Liver Disease
  • Place of Presentation: Boston, USA
• [Presentation] Bcl-xL and Mcl-1 cooperate to maintain integrity of hepatocytes (2009)
  • Author(s): Hikita H, Takehara T, et al.
  • Organizer: The American Association for the Study of Liver Diseases, 60^<th> Annual Meeting AASLD
  • Place of Presentation: Boston, USA
• [Remarks]
  • URL: http://www.med.osaka-u.ac.jp/pub/gh/index.htm
• [Remarks]
  • URL: http://www.med.osaka-u.ac.jp/pub/gh/data/relations/study_a.html
• [Remarks]
  • URL: http://www.med.osaka-u.ac.jp/pub/gh/data/relations/study_a.html
• [Remarks]
  • URL: http://www.med.osaka-u.ac.jp/pub/gh/data/relations/study_a.html