Glycogen synthase kinase-3 (GSK-3) inhibition attenuates hepatocyte lipoapoptosis

JOURNAL OF HEPATOLOGY

卷:54

Article

Akazawa, Yuko²  Billadeau, Daniel D.¹ 

[1] Mayo Clin, Div Oncol Res, Coll Med, Rochester, MN 55905 USA

[2] Nagasaki Univ, Sch Med, Dept Internal Med, Nagasaki 8528562, Japan

关键词: Endoplasmic reticulum stress;    Glycogen synthase kinase;    JNK;    Lipoapoptosis;    Non-alcoholic steatohepatitis;    PUMA;   

DOI  :  10.1016/j.jhep.2010.09.039

来源: Elsevier

【 摘 要 】

Backgrounds & Aims: Saturated free fatty acids induce hepatocyte lipoapoptosis, a key pathologic feature of non-alcoholic steatohepatitis. The saturated free fatty acid palmitate induces hepatocyte lipoapoptosis via an endoplasmic reticulum stress pathway resulting in c-Jun-N-terminal (JNK) activation. Glycogen synthase kinase (GSK)-3 is a serine/threonine kinase which may also promote JNK activation. Thus, our aim was to determine if GSK-3 inhibition suppresses palmitate induced JNK activation and lipoapoptosis. Methods: For these studies, we employed mouse primary hepatocytes, Huh-7 and Hep3B cell lines. Results: Palmitate-induced GSK-3 activation was identified by phosphorylation of its substrate glycogen synthase. GSK-3 pharmacologic inhibition, by GSK-3 inhibitor IX and enzastaurin, significantly reduced PA-mediated lipoapoptosis. More importantly, Huh-7 cells, in which either GSK-3 alpha or GSK-3 beta isoforms were stably and selectively knocked down by shRNA, displayed resistance to palmitate-induced cytotoxicity. GSK-3 pharmacological inhibitors and shRNA-targeted knockdown of GSK-3a or GSK-30 also suppressed JNK activation by palmitate. JNK activation, in part, promotes lipoapotosis by inducing expression of the pro-apoptotic effector p53-upregulated modulator of apoptosis (PUMA). Consistent with this concept, GSK-3 pharmacologic inhibition also reduced PUMA cellular protein levels during exposure to palmitate. On the other hand, the GSK-3 inhibitors did not prevent PA induction of ER stress. Conclusions: Our results suggest that GSK-3 activation promotes a JNK-dependent cytotoxic signaling cascade culminating in lipoapoptosis. (C) 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

【 授权许可】

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