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Involvement of the apelin receptor APJ in Fas-induced liver injury



Hiroaki Yasuzaki, Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine and School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan

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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.


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.


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.


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.