Sato-Matsubara, M; Matsubara, T; Daikoku, A; Okina, Y; Longato, L; Rombouts, K; Thuy, TTL; ... Kawada, N; + view all Sato-Matsubara, M; Matsubara, T; Daikoku, A; Okina, Y; Longato, L; Rombouts, K; Thuy, TTL; Adachi, J; Tomonaga, T; Ikeda, K; Yoshizato, K; Pinzani, M; Kawada, N; - view fewer (2017) Fibroblast growth factor 2 (FGF2) regulates cytoglobin expression and activation of human hepatic stellate cells via JNK signaling. Journal of Biological Chemistry , 292 (46) pp. 18961-18972. 10.1074/jbc.M117.793794.

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Abstract

Cytoglobin (CYGB) belongs to the mammalian globin family and is exclusively expressed in hepatic stellate cells (HSCs) in the liver. In addition to its gas-binding ability, CYGB is relevant to hepatic inflammation, fibrosis, and cancer because of its antioxidative properties; however, the regulation of CYGB gene expression remains unknown. Here, we sought to identify factors that induce CYGB expression in HSCs and to clarify the molecular mechanism involved. We used the human HSC cell line HHSteC and primary human HSCs isolated from intact human liver tissues. In HHSteC cells, treatment with a culture supplement that included fibroblast growth factor 2 (FGF2) increased CYGB expression with concomitant and time-dependent α-smooth muscle actin (αSMA) downregulation. We found that FGF2 is a key factor in inducing the alteration in both CYGB and αSMA expression in HHSteCs and primary HSCs and that FGF2 triggered the rapid phosphorylation of both c-Jun N′terminal kinase (JNK) and c-JUN. Both the JNK inhibitor PS600125 and transfection of c-JUN-targeting siRNA abrogated FGF2-mediated CYGB induction, and, conversely, c-JUN overexpression induced CYGB and reduced αSMA expression. Chromatin immunoprecipitation analyses revealed that upon FGF2 stimulation, phospho-c-JUN bound to its consensus motif (5′-TGAC/GTCA), located −218 to −222 bases from the transcription initiation site in the CYGB promoter. Of note, in bile duct-ligated mice, FGF2 administration ameliorated liver fibrosis and significantly reduced HSC activation. In conclusion, FGF2 triggers CYGB gene expression and deactivation of myofibroblastic human HSCs, indicating that FGF2 has therapeutic potential for managing liver fibrosis.

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