Valproate protects cells from ER stress-induced lipid accumulation and apoptosis by inhibiting glycogen synthase kinase-3.
A wide range of agents and conditions are known to disrupt the ability of the endoplasmic reticulum (ER) to fold proteins properly, resulting in the onset of ER dysfunction/stress. We and others have shown that ER stress can induce intracellular lipid accumulation through the activation of the sterol responsive element binding proteins (SREBPs) and initiate programmed cell death by activation of caspases. It has been suggested that ER stress-induced lipid accumulation and cell death play a role in the pathogenesis of disorders including Alzheimer's disease, Parkinson's disease, type-1 diabetes mellitus and hepatic steatosis. Here we show that exposure of HepG2 cells to the branch chain fatty acid, valproate, increases cellular resistance to ER stress-induced dysfunction. Two distinctly different potential mechanisms for this protective effect were investigated. We show that exposure to valproate increases the expression of chaperones that assist in the folding of proteins in the ER including GRP78/BiP, GRP94, PDI and calreticulin as well as the cytosolic chaperone, HSP70. However, exposure of HepG2 cells to valproate does not decrease the apparent ER stress response in cells challenged with tunicamycin, A23187 or glucosamine, suggesting that valproate-conferred protection occurs downstream of ER dysfunction. Finally, we demonstrate that valproate directly inhibits the glycogen synthase kinases (GSK)-3alpha/beta. The ability of lithium, another inhibitor of GSK3alpha/beta to protect cells from ER stress-induced lipid accumulation suggests that GSK3 plays a central role in signaling downstream effects of ER stress. Strategies to protect cells from agents/conditions that induce ER stress may have potential in the treatment of the growing number of diseases and disorders linked to ER dysfunction.
Kim
Anna J
AJ
Department of Biochemistry, McMaster University, Hamilton, Ontario, L8S 4LB, Canada.
Shi
Yuanyuan
Y
Austin
Richard C
RC
Werstuck
Geoff H
GH
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000187:drug effects; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D008055:Lipids / Q000096:biosynthesis*; D008113:Liver Neoplasms / Q000473:pathology; D013312:Stress, Physiological / Q000378:metabolism*; D014635:Valproic Acid / Q000494:pharmacology*
D000091342:Endoplasmic Reticulum Chaperone BiP; D004791:Enzyme Inhibitors; C000717247:HSPA5 protein, human; D008055:Lipids; D014635:Valproic Acid; D007770:L-Lactate Dehydrogenase; D038362:Glycogen Synthase Kinase 3