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

ABSTRACT:

Background

Reduction of pancreatic ?-cells mass, major secondary to increased ?-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 ?-cells apoptosis. Recent literature suggests that valproate, a diffusely prescribed drug in the treatment of epilepsy and bipolar disorder, can inhibit glycogen synthase kinase-3? (GSK-3?) activity and has cytoprotective effects in neuronal cells and HepG2 cells. Thus, we hypothesized that valproate may protect INS-1 ?-cells from palmitate-induced apoptosis via inhibiting GSK-3?.

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-3? and caspase-3 activity induced by palmitate, whereas, the mRNA expression of ATF4 was not affected. Interestingly, TDZD-8, a specific GSK-3? 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 ?-cells from palmitate-induced apoptosis and ER stress via GSK-3? inhibition, independent of ATF4/CHOP pathway. Besides, GSK-3?, rather than CHOP, may be a more promising therapeutic target for T2D.

SUBMITTER: Huang S 

PROVIDER: S-EPMC4084580 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature