The role of heparin-binding EGF-like growth factor in liver fibrosis

• Project/Area Number: 24590975
• 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(研究院), 特任准教授 (40335352)
• Co-Investigator(Kenkyū-buntansha): YOSHIDA Yuichi 大阪大学, 大学院医学系研究科, 助教 (30457014) ; WATABE Kenji 大阪大学, 医学部附属病院, 准教授 (50379244)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2013: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2012: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
• Keywords: 肝線維化 / 肝再生 / HB-EGF / 肝星細胞 / ノックアウトマウス / TGF-β

Outline of Final Research Achievements

We reported that Heparin-binding EGF-like growth factor (HB-EGF) was a hepatotropic factor in vivo. However, the role of HB-EGF in liver fibrosis remains still unclear. Our aim is to evaluate the involvement of HB-EGF in liver fibrogenesis of mice. Gene expression of HB-EGF was increased in bile duct ligation (BDL)-induced fibrotic livers. We generated conditional HB-EGF knockout (KO) mice and were subjected to BDL. After BDL, KO mice exhibited enhanced liver fibrosis with increased expression of collagen. Finally, we used mouse hepatic stellate cells (HSCs) to examine the role of HB-EGF in the activation of these cells and showed that HB-EGF antagonized TGF-β-induced gene expression of collagen in mouse primary HSCs. HB-EGF did not prevent the TGF-β-induced nuclear accumulation of Smad3, but did lead to stabilization of the Smad transcriptional co-repressor TG-interacting factor. In conclusion, our data suggest a possible protective role of HB-EGF in cholestatic liver fibrosis.

Research Products

• [Journal Article] Loss of Gab1 adaptor protein in hepatocytes aggravates experimental liver fibrosis in mice. (2015)
  • Author(s): Kizu T, Yoshida Y, Furuta K, Ogura S, Egawa M, Chatani N, Hamano M, Takemura T, Ezaki H, Kamada Y, Nishida K, Nakaoka Y, Kiso S, Takehara T.
  • Journal Title: Am J Physiol Gastrointest Liver Physiol Volume: 308 Issue: 7 Pages: 613-624
  • DOI: 10.1152/ajpgi.00289.2014
  • 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
• [Journal Article] The real impact of telaprevir dosage on the antiviral and side effects of telaprevir, pegylated interferon and ribavirin therapy for chronic hepatitis C patients with HCV genotype 1. (2015)
  • Author(s): Oze T, Hiramatsu N, Yoshida Y et al.
  • Journal Title: J Viral Hepat. Volume: 22 Issue: 3 Pages: 254-262
  • DOI: 10.1111/jvh.12289
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] The prospective randomized study on telaprevir at 1500 or 2250 mg with pegylated interferon plus ribavirin in Japanese patients with HCV genotype 1. (2015)
  • Author(s): Oze T, Hiramatsu N, Yoshida Y et al.
  • Journal Title: J Gastroenterol. Volume: 50 Issue: 3 Pages: 313-322
  • DOI: 10.1007/s00535-014-0965-8
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Risk factors for hepatocellular carcinoma in hepatitis C patients with normal ALT treated with pegylated interferon and ribavirin (2014)
  • Author(s): Harada N, Hiramatsu N, Oze T, Morishita N, Yamada R, Hikita H, Miyazaki M, Yakushijin T, Miyagi T, Yoshida Y, Tatsumi T, Kanto A, Kasahara A, Oshita M, Mita E, Hagiwara H, Inui Y, Katayama K, Shinji Tamura, Yoshihara H, Imai Y, Inoue A, Hayashi N, Takehara T
  • Journal Title: J Viral Hepat Volume: ２１ Issue: 5 Pages: 357-365
  • DOI: 10.1111/jvh.12151
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Conditional loss of heparin-binding EGF-like growth factor results in enhanced liver fibrosis after bile duct ligation in mice. (2013)
  • Author(s): Takemura T, Yoshida Y, Kiso S, Kizu T, Furuta K, Ezaki H, Hamano M, Egawa M, Chatani N, Kamada Y, Imai Y, Higashiyama S, Iwamoto R, Mekada E, Takehara T.
  • Journal Title: Biochem Biophys Res Commun. Volume: 437 Issue: 2 Pages: 185-191
  • DOI: 10.1016/j.bbrc.2013.05.097
  • Peer Reviewed
• [Journal Article] Serum Mac-2 binding protein levels as a novel diagnostic biomarker for prediction of disease severity and nonalcoholic steatohepatitis. (2013)
  • Author(s): Kamada Y, Fujii H, Fujii H, Sawai Y, Doi Y, Uozumi N, Mizutani K, Akita M, Sato M, Kida S, Kinoshita N, Maruyama N, Yakushijin T, Miyazaki M, Ezaki H, Hiramatsu N, Yoshida Y, Kiso S, Imai Y, Kawada N, Takehara T, Miyoshi E.
  • Journal Title: Proteomics Clin Appl Volume: 8(6)
  • Peer Reviewed
• [Journal Article] Serum Mac-2 binding protein levels as a novel diagnostic biomarker for prediction of disease severity and nonalcoholic steatohepatitis. (2013)
  • Author(s): Kamada Y, Fujii H,Miyoshi E,et.al.
  • Journal Title: Proteomics Clin Appl. Volume: 6 Issue: 9-10 Pages: 648-656
  • DOI: 10.1002/prca.201200137
  • Peer Reviewed
• [Presentation] Loss of Grb2-associated binder 1 results in enhanced hepatocyte necrosis and high mortality in mice with acute liver failure (2014)
  • Author(s): Kunimaro Furuta, Yuichi Yoshida, Takashi Kizu, Satoshi Ogura, Mayumi Egawa, Norihiro Chatani, Yoshihiro Kamada, Shinichi Kiso, Tetsuo Takehara
  • Organizer: 65th Annual Meeting of the American Association for the Study of Liver Diseases
  • Place of Presentation: John B. Hynes Veterans Memorial Convention Center, Boston, MA, USA
  • Year and Date: 2014-11-09
• [Presentation] Grb2-associated binder 1 protects against liver fibrosis via suppression of CCL5 production from hepatocytes (2014)
  • Author(s): Yuichi Yoshida, Takashi Kizu, Kunimaro Furuta, Satoshi Ogura, Mayumi Egawa, Norihiro Chatani, Yoshihiro Kamada, Shinichi Kiso, Tetsuo Takehara
  • Organizer: 65th Annual Meeting of the American Association for the Study of Liver Diseases
  • Place of Presentation: John B. Hynes Veterans Memorial Convention Center, Boston, MA, USA
  • Year and Date: 2014-11-09
• [Presentation] 急性肝不全におけるアダプター蛋白質Gab1を介した恒常性維持と治療標的としての可能性について (2014)
  • Author(s): 古田訓丸、吉田雄一、竹原徹郎
  • Organizer: 第18回日本肝臓学会大会
  • Place of Presentation: 神戸国際会議場（神戸）
  • Year and Date: 2014-10-23
• [Presentation] 肝細胞壊死を起点とした再生／恒常性維持の“鍵分子”としてのGab１の意義 (2014)
  • Author(s): 吉田雄一, 古田訓丸, 竹原徹郎
  • Organizer: 第50回日本肝臓学会総会
  • Place of Presentation: ホテルニューオータニ（東京）
  • Year and Date: 2014-05-29
• [Presentation] 肝線維化に対する新規治療標的としての肝細胞Gab１‐CCL５経路の意義 (2014)
  • Author(s): 吉田雄一, 木津崇, 古田訓丸, 小倉智志, 柄川真弓, 茶谷徳啓, 江崎久男, 鎌田佳宏, 木曽真一, 竹原徹郎
  • Organizer: 第50回日本肝臓学会総会
  • Place of Presentation: ホテルニューオータニ（東京）
  • Year and Date: 2014-05-29
• [Presentation] Grb2-associated binder 1 docking protein is crucial for mortality in a mouse model of acute liver failure (2013)
  • Author(s): Furuta K, Yoshida Y, Kizu T, Ogura S, Egawa M, Chatani N, Hamano M, Ezaki H, Kamada Y, Kiso S, Takehara T
  • Organizer: The 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD2013)
  • Place of Presentation: Washington,DC, USA
• [Presentation] Serum Mac-2 binding protein levels as a novel diagnostic biomarker for prediction of disease severity and nonalcoholic steatohepatitis (2013)
  • Author(s): Kamada Y, Fujii H, Fujii H, Doi Y, Mizutani K, Akita M, Sato M, Kida S, Kinoshita N, Maruyama N, Yakushijin T, Miyazaki M, Ezaki H, Hiramatsu N, Yoshida Y, Kiso S, Kawada N, Takehara T, Miyoshi E
  • Organizer: The 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD2013)
  • Place of Presentation: Washington,DC, USA
• [Presentation] Loss of Gab1 scaffolding adaptor protein in the hepatocytes exacerbates cholestasis-induced liver fibrosis in mice (2013)
  • Author(s): Kizu T, Yoshida Y, Furuta K, Ogura S, Egawa M, Chatani N, Hamano M, Ezaki H, Kamada Y, Kiso S, Takehara T
  • Organizer: The 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD2013)
  • Place of Presentation: Washington,DC, USA
• [Presentation] HB-EGF (heparin-binding EGF-like growth factor) は肝線維化に対して抑制的に働く：遺伝子欠損マウスおよび培養肝星細胞を用いた検討 (2012)
  • Author(s): 竹村貴代、吉田雄一、古田訓丸、木津崇、柄川真弓、茶谷徳啓、濱野美奈、江崎久男、鎌田佳宏、木曽真一、竹原徹郎
  • Organizer: 第48回日本肝臓学会総会
  • Place of Presentation: 金沢
• [Presentation] Heparin-binding EGF-like growth factor（HB-EGF）による肝線維化制御：TGF-βシグナルとのクロストークについて (2012)
  • Author(s): 竹村貴代、吉田雄一、古田訓丸、木津崇、柄川真弓、茶谷徳啓、濱野美奈、江崎久男、松本仁、鎌田佳宏、木曽真一、竹原徹郎
  • Organizer: 第54回日本消化器病学会大会
  • Place of Presentation: 神戸