The role of Gab1 adaptor protein during stem /progenitor cell-mediated liver regeneration in acute liver failure

• Project/Area Number: 15K08997
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Osaka University
• Principal Investigator: KISO SHINICHI 大阪大学, 医学系研究科, 特任准教授 (40335352)
• Co-Investigator(Kenkyū-buntansha): 吉田 雄一 大阪大学, 医学系研究科, 特任助教 (30457014)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: Gab1 / 重症肝不全 / 肝再生 / 幹細胞 / 肝幹/前駆細胞

Outline of Final Research Achievements

In this study, we assessed the role of Gab1 in stem/progenitor cell-mediated liver regeneration using chemically induced model. To induce the adult hepatic stem/progenitor cells, the wild type (WT) and hepatocyte specific Gab1 conditional knockout (CKO) mice were treated with 0.1% of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet for 2-6 weeks. Liver to body weight ratio of CKO mice was significantly lower than that of WT mice at 2, 4 and 6 week after DDC exposure. CKO mice also had a significant higher mortality compared to WT mice due to severe cholestasis. The induction of the CK19 positive adult hepatic stem/progenitor cells was reduced in CKO livers compared with WT livers. Consistently, the gene expression of hepatic stem cell markers, such as EpCAM and CD133/Prominin1 was significantly reduced in CKO livers compared with WT livers. These data showed that Gab1 might play a crucial role in stem/progenitor cell-mediated liver regeneration.

Research Products

• [Journal Article] Increased expression of Forkhead box M1 transcription factor is associated with clinicopathological features and confers a poor prognosis in human hepatocellular carcinoma. (2017)
  • Author(s): Egawa M, Yoshida Y, Ogura S, Kurahashi T, Kizu T, Furuta K, Kamada Y, Chatani N, Hamano M, Kiso S, Hikita H, Tatsumi T, Eguchi H, Nagano H, Doki Y, Mori M, Takehara T
  • Journal Title: Hepatol Res. Volume: 印刷中 Issue: 11 Pages: 1196-1205
  • DOI: 10.1111/hepr.12854
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Ultra-deep sequencing analysis of resistance-associated variants during retreatment with simeprevir-based triple therapy after failure of telaprevir-based triple therapy in patients with genotype 1 hepatitis C virus infection. (2017)
  • Author(s): Morishita N, Hiramatsu N, Oze T, Urabe A, Tahata Y, Yamada R, Yakushijin T, Hosui A, Iio S, Yamada A, Hagiwara H, Mita E, Yamada Y, Ito T, Inada M, Katayama K, Yabuuchi I, Imai Y, Hikita H, Sakamori R, Yoshida Y, Tatsumi T, Hayashi N, Takehara T.
  • Journal Title: Hepatol Res. Volume: 印刷中 Issue: 8 Pages: 773-782
  • DOI: 10.1111/hepr.12817
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Hepatic aberrant glycosylation by N-acetylglucosaminyltransferase V accelerates HDL assembly. (2016)
  • Author(s): Kamada Y, Kida S, Hirano KI, Yamaguchi S, Suzuki A, Hashimoto C, Kimura A, Sato M, Fujii H, Sobajima T, Yamamoto A, Ebisutani Y, Takamatsu S, Shinzaki S, Yoshida Y, Yamada M, Nagasaka H, Takehara T, Miyoshi E.
  • Journal Title: Am J Physiol Gastrointest Liver Physiol. Volume: 311
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Gab1 adaptor protein acts as a gatekeeper to balance hepatocyte death and proliferation during acetaminophen-induced liver injury in mice. (2016)
  • Author(s): Furuta K, Yoshida Y, Ogura S, Kurahashi T, Kizu T, Maeda S, Egawa M, Chatani N, Nishida K, Nakaoka Y, Kiso S, Kamada Y, Takehara T.
  • Journal Title: Hepatology Volume: 63 Issue: 4 Pages: 1340-1355
  • DOI: 10.1002/hep.28410
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] The impact of an inosine triphosphate pyrophosphatase genotype on bilirubin increase in chronic hepatitis C patients treated with simeprevir, pegylated interferon plus ribavirin. (2016)
  • Author(s): Tahata Y, Hiramatsu N, Oze T, Morishita N, Harada N, Yamada R, Yakushijin T, Mita E, Hagiwara H, Yamada Y, Ito T, Hijioka T, Inada M, Katayama K, Tamura S, Yoshihara H, Inoue A, Imai Y, Irishio K, Kato M, Hikita H, Sakamori R, Miyagi T, Yoshida Y, Tatsumi T, Hamasaki T, Hayashi N, Takehara T
  • Journal Title: J Gastroenterol. Volume: 51 Pages: 252-259
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Ectopic expression of N-acetylglucosaminyltransferase V accelerates hepatic triglyceride synthesis. (2016)
  • Author(s): Kamada Y, Ebisutani Y, Kida S, Mizutani K, Akita M, Yamamoto A, Fujii H, Sobajima T, Terao N, Takamatsu S, Yoshida Y, Takehara T, Miyoshi E
  • Journal Title: Hepatol Res. Volume: 46 Issue: 3 Pages: 1189-129
  • DOI: 10.1111/hepr.12541
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] A novel noninvasive diagnostic method for nonalcoholic steatohepatitis using two glycobiomarkers. (2015)
  • Author(s): Kamada Y, Ono M, Hyogo H, Fujii H, Sumida Y, Mori K, Tanaka S, Yamada M, Akita M, Mizutani K, Fujii H, Yamamoto A, Takamatsu S, Yoshida Y, Itoh Y, Kawada N, Chayama K, Saibara T, Takehara T, Miyoshi E
  • Journal Title: Hepatology. Volume: 62 Issue: 5 Pages: 1433-1443
  • DOI: 10.1002/hep.28002
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Fetuin-A negatively correlates with liver and vascular fibrosis in nonalcoholic fatty liver disease subjects. (2015)
  • Author(s): Kamada Y*, Sato M* (equally contributed), Takeda Y, Kida S, Ohara Y, Fujii H, Akita M, Mizutani K, Yoshida Y, Yamada M, Hougaku H, Takehara T, Miyoshi E.
  • Journal Title: Liver Int Volume: 35 Issue: 3 Pages: 925-35
  • DOI: 10.1111/liv.12478
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] 慢性肝疾患における新規炎症制御因子としてのFoxM1転写因子の意義 (2017)
  • Author(s): 倉橋知英、吉田雄一、小倉智志、柄川真弓、古田訓丸、鎌田佳宏、木曽真一、疋田隼人、巽智秀、竹原徹郎
  • Organizer: 第53回日本肝臓学会総会
• [Presentation] NAFLD病態進展における肝細胞FoxM1転写因子の役割 (2017)
  • Author(s): 倉橋知英、吉田雄一、小倉智志、柄川真弓、古田訓丸、鎌田佳宏、木曽真一、疋田隼人、巽智秀、竹原徹郎
  • Organizer: 第42回日本肝臓学会西部会
• [Presentation] Lipid metabolism regulates oncogenic FoxM1 transcription factor in human hepatocellular carcinoma via the mevalonate-Rho pathway (2017)
  • Author(s): Yuichi Yoshida, Satoshi Ogura, Tomohide Kurahashi, Mayumi Egawa, Kunimaro Furuta, Shinichi Kiso, Yoshihiro Kamada, Hayato Hikita, Tomohide Tatsumi and Tetsuo Takehara
  • Organizer: 第68回米国肝臓学会議
  • Int'l Joint Research
• [Presentation] Overexpression of FoxM1 transcription factor in murine hepatocytes results in hepatocyte death and liver inflammation (2017)
  • Author(s): Tomohide Kurahashi, Yuichi Yoshida, Satoshi Ogura, Mayumi Egawa, Kunimaro Furuta, Yoshihiro Kamada, Shinichi Kiso, Hayato Hikita, Tomohide Tatsumi, Tetsuo Takehara
  • Organizer: 第68回米国肝臓学会議
  • Int'l Joint Research
• [Presentation] FoxM1転写因子による慢性肝疾患の制御機構：新規マウスモデルを用いた検討 (2016)
  • Author(s): 倉橋知英、吉田雄一、小倉智志、柄川真弓、古田訓丸、鎌田佳宏、木曽真一、疋田隼人、巽智秀、竹原徹郎
  • Organizer: 第41回日本肝臓学会東部会
  • Place of Presentation: 京王プラザホテル（東京都新宿区)
  • Year and Date: 2016-12-08
• [Presentation] FoxM1転写因子を介した癌脂質代謝プログラムに基づく新たな肝癌治療戦略 (2016)
  • Author(s): 小倉智志、吉田雄一、倉橋知英、柄川真弓、古田訓丸、木曽真一、鎌田佳宏、疋田隼人、 巽智秀、竹原徹郎
  • Organizer: 第41回日本肝臓学会東部会
  • Place of Presentation: 京王プラザホテル（東京都新宿区）
  • Year and Date: 2016-12-08
• [Presentation] Metabolic regulation of FoxM1 transcription factor by mevalonate-Rho pathways in human hepatocarcinoma. (2016)
  • Author(s): Satoshi Ogura, Yuichi Yoshida, Tomohide Kurahashi, Mayumi Egawa, Kunimaro Furuta, Shinichi Kiso, Yoshihiro Kamada, Hayato Hikita, Tomohide Tatsumi and Tetsuo Takehara.
  • Organizer: The Liver Meeting 2016 - AASLD
  • Place of Presentation: HYNES CONVENTION CENTER, BOSTON, MA, USA
  • Year and Date: 2016-11-11
  • Int'l Joint Research
• [Presentation] Hepatic overexpression of oncogenic FoxM1 transcription factor promotes hepatocyte death and hepatic inflammation in mice. (2016)
  • Author(s): Tomohide Kurahashi, Yuichi Yoshida, Satoshi Ogura, Mayumi Egawa, Kunimaro Furuta, Yoshihiro Kamada, Shinichi Kiso, Hayato Hikita, Tomohide Tatsumi, Tetsuo Takehara.
  • Organizer: The Liver Meeting 2016 - AASLD
  • Place of Presentation: HYNES CONVENTION CENTER, BOSTON, MA, USA
  • Year and Date: 2016-11-11
  • Int'l Joint Research
• [Presentation] 肝癌における癌脂質代謝経路の意義とFoxM1の関与について (2016)
  • Author(s): 小倉智志、吉田雄一、竹原徹郎
  • Organizer: 第24回 日本消化器関連学会週間
  • Place of Presentation: 神戸コンベンションセンター（兵庫県神戸市中央区）
  • Year and Date: 2016-11-03
• [Presentation] 癌脂質代謝からみた肝癌制御の可能性：Rho/YAP/FoxM1 経路の意義 (2016)
  • Author(s): 小倉智志、吉田雄一、竹原徹郎
  • Organizer: 第52回日本肝臓学会総会
  • Place of Presentation: ホテルニューオータニ幕張（千葉県千葉市美浜区）
  • Year and Date: 2016-05-19
• [Presentation] 急性肝不全病態においてGab1 は肝細胞運命の決定を担う (2016)
  • Author(s): 古田訓丸, 吉田雄一, 倉橋知英, 小倉智志, 柄川真弓, 木曽真一, 鎌田佳宏, 竹原徹郎
  • Organizer: 第52回日本肝臓学会総会
  • Place of Presentation: ホテルニューオータニ幕張（千葉県千葉市美浜区）
  • Year and Date: 2016-05-19
• [Presentation] FoxM1 転写因子を介した新たな肝癌脂質代謝制御：治療標的としての可能性について (2016)
  • Author(s): 小倉智志、吉田雄一、柄川真弓、倉橋 知英、古田訓丸、木曽真一、鎌田佳宏、竹原徹郎
  • Organizer: 第102回 日本消化器病学会総会
  • Place of Presentation: 京王プラザホテル（東京都新宿区)
  • Year and Date: 2016-04-21
• [Presentation] 肝癌脂質代謝におけるFoxM1転写因子を介したシグナル経路の意義 (2015)
  • Author(s): 小倉智志、吉田雄一、竹原徹郎
  • Organizer: 第41回日本肝臓学会西部会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2015-12-03
• [Presentation] Gab1 adaptor protein is an essential gatekeeper to balance hepatocyte death and proliferation during acetaminophen-induced liver injury in mice (2015)
  • Author(s): Yuichi Yoshida, Kunimaro Furuta, Satoshi Ogura, Tomohide Kurahashi, Mayumi Egawa, Shinichi Kiso, Yoshihiro Kamada, and Tetsuo Takehara
  • Organizer: 第66回米国肝臓学会議
  • Place of Presentation: Moscone Convention Center, San Francisco, USA
  • Year and Date: 2015-11-17
  • Int'l Joint Research
• [Presentation] A novel noninvasive diagnostic method for nonalcoholic steatohepatitis (NASH) using two glycobiomarkers (2015)
  • Author(s): Yoshihiro Kamada, Masafumi Ono, Hideyuki Hyogo, Hideki Fujii, Yoshio Sumida, Kohjiroh Mori, Saiyu Tanaka, Makoto Yamada, Maaya Akita, Kayo Mizutani, Hironobu Fujii, Akiko Yamamoto, Shinji Takamatsu, Yuichi Yoshida, Yoshito Itoh, Norifumi Kawada, Kazuaki Chayama, Toshiji Saibara, Tetsuo Takehara, Eiji Miyoshi
  • Organizer: 第66回米国肝臓学会議
  • Place of Presentation: Moscone Convention Center, San Francisco, USA
  • Year and Date: 2015-11-17
  • Int'l Joint Research
• [Presentation] 肝細胞癌におけるHMG-CoA還元酵素阻害剤によるFoxM1転写因子の発現制御 (2015)
  • Author(s): 小倉智志、吉田雄一、柄川真弓、古田訓丸、木津 崇、木曽真一、鎌田佳宏、竹原徹郎
  • Organizer: 第23回JDDW
  • Place of Presentation: グランドプリンスホテル新高輪
  • Year and Date: 2015-10-08
• [Presentation] 肝細胞癌におけるメバロン酸経路を介したFoxM1転写因子の制御と臨床応用の可能性について (2015)
  • Author(s): 小倉智志、吉田雄一、柄川真弓、古田訓丸、木津 崇、木曽真一、鎌田佳宏、竹原徹郎
  • Organizer: 第51回日本肝臓学会総会
  • Place of Presentation: ホテル日航熊本
  • Year and Date: 2015-05-22
• [Presentation] 重症肝不全病態における ストレス応答制御分子としての 肝細胞 Gab1 の意義と治療標的としての可能性 (2015)
  • Author(s): 古田訓丸, 吉田雄一, 木津崇, 小倉智志, 柄川真弓, 茶谷徳啓, 鎌田佳宏, 木曽真一, 竹原徹郎
  • Organizer: 第51回日本肝臓学会総会
  • Place of Presentation: ホテル日航熊本
  • Year and Date: 2015-05-21