Conditional knockout of heparin-binding epidermal growth factor-like growth factor in the liver accelerates carbon tetrachloride-induced liver injury in mice
Takayo Takemura
Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine
Search for more papers by this authorYuichi Yoshida
Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine
Search for more papers by this authorCorresponding Author
Shinichi Kiso
Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine
Dr Shinichi Kiso, Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine, 2-2 K1 Yamadaoka, Suita, Osaka 565-0871, Japan. Email: [email protected]Search for more papers by this authorYukiko Saji
Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine
Search for more papers by this authorHisao Ezaki
Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine
Search for more papers by this authorMina Hamano
Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine
Search for more papers by this authorTakashi Kizu
Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine
Search for more papers by this authorMayumi Egawa
Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine
Search for more papers by this authorNorihiro Chatani
Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine
Search for more papers by this authorKunimaro Furuta
Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine
Search for more papers by this authorYoshihiro Kamada
Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine
Search for more papers by this authorRyo Iwamoto
Department of Cell Biology, Research Institute for Microbial Diseases, Osaka University, Osaka
Search for more papers by this authorEisuke Mekada
Department of Cell Biology, Research Institute for Microbial Diseases, Osaka University, Osaka
Search for more papers by this authorShigeki Higashiyama
Department of Biochemistry and Molecular Genetics, Ehime University, Graduate School of Medicine
Department of Cell Growth and Tumor Regulation, Proteo-Medicine Research Center (ProMRes), Ehime University, Ehime
Search for more papers by this authorTetsuo Takehara
Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine
Search for more papers by this authorTakayo Takemura
Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine
Search for more papers by this authorYuichi Yoshida
Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine
Search for more papers by this authorCorresponding Author
Shinichi Kiso
Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine
Dr Shinichi Kiso, Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine, 2-2 K1 Yamadaoka, Suita, Osaka 565-0871, Japan. Email: [email protected]Search for more papers by this authorYukiko Saji
Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine
Search for more papers by this authorHisao Ezaki
Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine
Search for more papers by this authorMina Hamano
Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine
Search for more papers by this authorTakashi Kizu
Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine
Search for more papers by this authorMayumi Egawa
Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine
Search for more papers by this authorNorihiro Chatani
Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine
Search for more papers by this authorKunimaro Furuta
Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine
Search for more papers by this authorYoshihiro Kamada
Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine
Search for more papers by this authorRyo Iwamoto
Department of Cell Biology, Research Institute for Microbial Diseases, Osaka University, Osaka
Search for more papers by this authorEisuke Mekada
Department of Cell Biology, Research Institute for Microbial Diseases, Osaka University, Osaka
Search for more papers by this authorShigeki Higashiyama
Department of Biochemistry and Molecular Genetics, Ehime University, Graduate School of Medicine
Department of Cell Growth and Tumor Regulation, Proteo-Medicine Research Center (ProMRes), Ehime University, Ehime
Search for more papers by this authorTetsuo Takehara
Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine
Search for more papers by this authorConflict of interest: none.
Author contributions: T. K.: study concept and design, acquisition, analysis and interpretation of data, drafting of manuscript; Y. Y.: study concept and design, analysis and interpretation of data, drafting of manuscript; Y. S., H. E., M. H., T. K., M. T., N. C., K. F., Y. K., R. I., E. M., S. H.: interpretation of data; N. H.: study concept, design; S. K.: study concept and design, analysis and interpretation of data, drafting of manuscript; and T. T.: study concept, design and supervision
Abstract
Aim: We previously demonstrated that heparin-binding epidermal growth factor-like growth factor (HB-EGF) is induced in response to several liver injuries. Because the HB-EGF knockout (KO) mice die in utero or immediately after birth due to cardiac defects, the loss of function study in vivo is limited. Here, we generated liver-specific HB-EGF conditional knockout mice using the interferon-inducible Mx-1 promoter driven cre recombinase transgene and investigated its role during acute liver injury.
Methods: We induced acute liver injury by a single i.p. injection of carbon tetrachloride (CCl4) in HB-EGF KO mice and wild-type mice and liver damage was assessed by biochemical and immunohistochemical analysis. We also used AML12 mouse hepatocyte cell lines to examine the molecular mechanism of HB-EGF-dependent anti-apoptosis and wound-healing process of the liver in vitro.
Results: HB-EGF KO mice exhibited a significant increase of alanine aminotransferase level and also showed a significant increase in the number of apoptotic hepatocytes assessed by terminal deoxynucleotidyl transferase dUTP nick end labeling staining at 24 h after CCl4 injection. We also demonstrated that HB-EGF treatment inhibited tumor necrosis factor-α-induced apoptosis of AML12 mouse hepatocytes and promoted the wound-healing response of these cells.
Conclusion: This study showed that HB-EGF plays a protective role during acute liver injury.
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