Abstract
BackgroundReduction 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.ResultsValproate 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.ConclusionsValproate 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.
Highlights
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
If homeostasis fails to be restored, the ER stress would initiate apoptosis pathways [6]. β-cells, due to their heavy engagement in insulin secretion, have been found to be very sensitive to disruptions in ER homeostasis [7,8], and accumulating evidence suggests that saturated free fatty acids (FFAs), such as palmitate, have been shown to trigger ER stress that may contribute to promoting β-cells apoptosis [9]
(B) With or without VPA pretreatment for 48 h, INS-1 cells were exposed to 0.25 mM PA for 24 h, cell viability was assessed by cell counting kit-8 (CCK-8) assay
Summary
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. Reduction of β-cells mass, mainly due to increased apoptosis, is increasingly recognized as one of the key contributing factors to. Β-cells, due to their heavy engagement in insulin secretion, have been found to be very sensitive to disruptions in ER homeostasis [7,8], and accumulating evidence suggests that saturated free fatty acids (FFAs), such as palmitate, have been shown to trigger ER stress that may contribute to promoting β-cells apoptosis [9] If homeostasis fails to be restored, the ER stress would initiate apoptosis pathways [6]. β-cells, due to their heavy engagement in insulin secretion, have been found to be very sensitive to disruptions in ER homeostasis [7,8], and accumulating evidence suggests that saturated free fatty acids (FFAs), such as palmitate, have been shown to trigger ER stress that may contribute to promoting β-cells apoptosis [9]
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