title: Involvement of the apelin receptor APJ in Fas-induced liver injury.
abstract: BACKGROUND
  Apelin-APJ signalling is known to play important roles in heart physiology and pathology; however, its functions in liver physiology and pathology remain unclear. On the other hand, Fas is an important molecule in hepatitis and other liver disease that belongs to the death receptor family. The aim of this study was to assess the relationship between apelin-APJ signaling and Fas-mediated liver injury in mice.
  
  
  METHODS
  APJ(-/-) mice and wild type (WT) mice were administered an intraperitoneal injection of an agonistic anti-Fas antibody (clone; Jo2), and sacrificed after 3 or 6 h to assess the liver histology. The expression levels of apelin and APJ, plasma levels of transaminases, activities of hepatic caspases and activations of stress-activated protein kinases were also analysed.
  
  
  RESULTS
  Before the Jo2 injection, APJ was weakly expressed in the hepatocytes in spots; on the other hand, after the Jo2 injection, it had spread into whole hepatocytes. Moreover, the mRNA expression level of apelin and APJ in the liver increased after Jo2 injection. In the APJ(-/-) mice, the liver injuries and apoptotic changes were significantly inhibited as compared with those in the WT mice. Dramatic increase in JNK activation was observed in the WT mice after Jo2 injection, whereas such activation was completely absent in the APJ(-/-) mice. JNK inhibitor partially, but significantly suppressed Jo2-mediated liver injury in WT mice.
  
  
  CONCLUSIONS
  Apelin-APJ signalling may promote Fas-induced liver injury at least partially via JNK activation, and may thus serve as a potential therapeutic target in cases of acute liver injury.
authors.affiliation: Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Yasuzaki
authors.forename: Shin-ichirou
authors.initials: S
authors.lastname: Yoshida
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Hashimoto
authors.forename: Wataru
authors.initials: W
authors.lastname: Shibata
authors.forename: Masahiko
authors.initials: M
authors.lastname: Inamori
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Toya
authors.forename: Kouichi
authors.initials: K
authors.lastname: Tamura
authors.forename: Shin
authors.initials: S
authors.lastname: Maeda
authors.forename: Satoshi
authors.initials: S
authors.lastname: Umemura
mesh_terms: D054392:Adipokines; D000818:Animals; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000073861:Apelin; D000075244:Apelin Receptors; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008107:Liver Diseases / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D054392:Adipokines; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000073861:Apelin; D000075244:Apelin Receptors; C402826:Apln protein, mouse; C491285:Aplnr protein, mouse; C491899:Fas protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; C411023:anti-Fas monoclonal antibody; D019014:fas Receptor; D048031:JNK Mitogen-Activated Protein Kinases; D020169:Caspases