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

Samar H. Ibrahim, Yuko Akazawa, Sophie C. Cazanave, Steven F. Bronk, Nafisa A. Elmi, Nathan W. Werneburg, Daniel D. Billadeau, Gregory J. Gores

Research output: Contribution to journalArticlepeer-review

61 Scopus citations

Abstract

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-3α or GSK-3β 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-3α or GSK-3β 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.

Original languageEnglish (US)
Pages (from-to)765-772
Number of pages8
JournalJournal of hepatology
Volume54
Issue number4
DOIs
StatePublished - Apr 2011

Keywords

  • Endoplasmic reticulum stress
  • Glycogen synthase kinase
  • JNK
  • Lipoapoptosis
  • Non-alcoholic steatohepatitis
  • PUMA

ASJC Scopus subject areas

  • Hepatology

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