title: Valproate pretreatment protects pancreatic β-cells from palmitate-induced ER stress and apoptosis by inhibiting glycogen synthase kinase-3β.
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.
authors.forename: Shan
authors.initials: S
authors.lastname: Huang
authors.forename: Minghui
authors.initials: M
authors.lastname: Zhu
authors.forename: Wei
authors.initials: W
authors.lastname: Wu
authors.forename: Abid
authors.initials: A
authors.lastname: Rashid
authors.forename: Yan
authors.initials: Y
authors.lastname: Liang
authors.forename: Ling
authors.initials: L
authors.lastname: Hou
authors.forename: Qin
authors.initials: Q
authors.lastname: Ning
authors.affiliation: Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No,1095, Jiefang Avenue, Wuhan, Hubei Province 430030, P,R, China. xpluo@tjh.tjmu.edu.cn.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Luo
mesh_terms: D051701:Activating Transcription Factor 4 / Q000096:biosynthesis; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D050417:Insulin-Secreting Cells / Q000187:drug effects*; D010168:Palmitates / Q000008:administration & dosage; D051381:Rats; D051742:Transcription Factor CHOP / Q000096:biosynthesis; D014635:Valproic Acid / Q000008:administration & dosage*
chemical_list: C497110:Atf4 protein, rat; C497251:Ddit3 protein, rat; D010168:Palmitates; D051701:Activating Transcription Factor 4; D051742:Transcription Factor CHOP; D014635:Valproic Acid; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3