- 作者: Shan Huang, Minghui Zhu, Wei Wu, Abid Rashid, Yan Liang, Ling Hou, Qin Ning ,Xiaoping Luo
- 作者服務機構: Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue, Wuhan, Hubei Province , P.R. China
- 中文摘要: --
- 英文摘要:
Background:
Reduction of pancreatic beta-cells mass, major secondary to increased beta-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 beta-cells apoptosis. Recent literature suggests that valproate, a diffusely prescribed drug in the treatment of epilepsy and bipolar disorder, can inhibit glycogen synthase kinase-3beta (GSK-3beta) activity and has cytoprotective effects in neuronal cells and HepG2 cells. Thus, we hypothesized that valproate may protect INS-1 beta-cells from palmitate-induced apoptosis via inhibiting GSK-3beta.
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-3beta and caspase-3 activity induced by palmitate, whereas, the mRNA expression of ATF4 was not affected. Interestingly, TDZD-8, a specific GSK-3beta 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 beta-cells from palmitate-induced apoptosis and ER stress via GSK-3beta inhibition, independent of ATF4/CHOP pathway. Besides, GSK-3beta, rather than CHOP, may be a more promising therapeutic target for T2D. - 中文關鍵字: --
- 英文關鍵字: Valproate, Endoplasmic reticulum stress, Glycogen synthase kinase-3β, Pancreatic β-cells, Apoptosis