Valproate pretreatment protects pancreatic β-cells from palmitate-induced ER stress and apoptosis by inhibiting glycogen synthase kinase-3β

33Citations
Citations of this article
37Readers
Mendeley users who have this article in their library.

This article is free to access.

Abstract

Background: Reduction of pancreatic β-cells mass, major secondary to increased β-cells apoptosis, is increasingly recognized as one of the main contributing factors to the pathogenesis of type 2 diabetes (T2D), and saturated free fatty acid palmitate has been shown to induce endoplasmic reticulum (ER) stress that may contribute to promoting β-cells apoptosis. Recent literature suggests that valproate, a diffusely prescribed drug in the treatment of epilepsy and bipolar disorder, can inhibit glycogen synthase kinase-3β (GSK-3β) activity and has cytoprotective effects in neuronal cells and HepG2 cells. Thus, we hypothesized that valproate may protect INS-1 β-cells from palmitate-induced apoptosis via inhibiting GSK-3β. Results: Valproate pretreatment remarkable prevented palmitate-mediated cytotoxicity and apoptosis (lipotoxicity) as well as ER distension. Furthermore, palmitate triggered ER stress as evidenced by increased mRNA levels of C/EBP homologous protein (CHOP) and activating transcription factor 4 (ATF4) in a time-dependent fashion. However, valproate not only reduced the mRNA and protein expression of CHOP but also inhibited GSK-3β and caspase-3 activity induced by palmitate, whereas, the mRNA expression of ATF4 was not affected. Interestingly, TDZD-8, a specific GSK-3β inhibitor, also showed the similar effect on lipotoxicity and ER stress as valproate in INS-1 cells. Finally, compared with CHOP knockdown, valproate displayed better cytoprotection against palmitate. Conclusions: Valproate may protect β-cells from palmitate-induced apoptosis and ER stress via GSK-3β inhibition, independent of ATF4/CHOP pathway. Besides, GSK-3β, rather than CHOP, may be a more promising therapeutic target for T2D. © 2014Huang et al.; licensee BioMed Central Ltd.

Cite

CITATION STYLE

APA

Huang, S., Zhu, M., Wu, W., Rashid, A., Liang, Y., Hou, L., … Luo, X. (2014). Valproate pretreatment protects pancreatic β-cells from palmitate-induced ER stress and apoptosis by inhibiting glycogen synthase kinase-3β. Journal of Biomedical Science, 21(1). https://doi.org/10.1186/1423-0127-21-38

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Save time finding and organizing research with Mendeley

Sign up for free