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Zhuang, Shaoyong; Hua, Xiangwei; He, Kang; Zhou, Tao; Zhang, Jiang; Wu, Haoyu; Ma, Xiong; Xia, Qiang; Zhang, Jianjun (2018): Inhibition of GSK-3 induces AP-1-mediated osteopontin expression to promote cholestatic liver fibrosis. In: FASEB Journal, Vol. 32, No. 8: pp. 4494-4503
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Abstract

The contribution of glycogen synthase kinase-3 (GSK-3) to cholestatic liver disease (CLD) remains unknown. We investigated the role and mechanism of GSK-3 in vivo in liver tissues of patients with CLD and the bile duct ligation (BDL) mouse model and in vitro using a hepatic progenitor cell (HPC) and hepatic stellate cell (HSC) coculture system. In liver tissues of patients with CLD, expression of the inactive form of GSK-3, phospho-GSK-3(Ser9), was increased in HPCs. GSK-3 inhibition by SB216763 treatment aggravated liver fibrosis and elevated the expression of osteopontin (OPN) in the BDL mouse model. OPN was significantly overexpressed in liver tissues and serum from patients with CLD. In an HPC and HSC coculture system, inhibition of GSK-3 induced OPN production, which activated HSCs in a cholestatic environment. The expression of activator protein 1 (AP-1), an important downstream transcription factor of GSK-3, was significantly increased in liver tissues of patients with CLD and SB216763-treated BDL mice. Finally, OPN expression was directly modulated by AP-1. These observations indicate that GSK-3 inhibition up-regulates OPN expression via AP-1 activation, which accelerates the progression of cholestatic liver fibrosis in patients with CLD and in BDL mice.Zhuang, S., Hua, X., He, K., Zhou, T., Zhang, J., Wu, H., Ma, X., Xia, Q., Zhang, J. Inhibition of GSK-3 induces AP-1-mediated osteopontin expression to promote cholestatic liver fibrosis.