Valproate protects cells from ER stress-induced lipid accumulation and apoptosis by inhibiting glycogen synthase kinase-3
Valproate protects cells from ER stress-induced lipid accumulation and apoptosis by inhibiting glycogen synthase kinase-3
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DOI：
10.1242/jcs.01562
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发表时间：
2005-01-01
影响因子：
4
通讯作者：
Werstuck, GH
中科院分区：
文献类型：
--
作者：
Kim, AJ;Shi, YY;Werstuck, GH
已知各种各样的药物和条件会破坏内质网（ER）正确折叠蛋白质的能力，导致内质网功能障碍/应激的发生。我们和其他人已经证明内质网应激可以通过激活甾醇反应元件结合蛋白（SREBPs）诱导细胞内脂质积累，并通过激活半胱天酶启动程序性细胞死亡。有研究表明内质网应激诱导的脂质积累和细胞死亡在阿尔茨海默病、帕金森病、1型糖尿病和肝脂肪变性等疾病的发病机制中起作用。本研究表明，HepG2细胞暴露于支链脂肪酸丙戊酸，可增加细胞对内质网应激诱导功能障碍的抵抗力。研究了这种保护作用的两种截然不同的潜在机制。研究表明，丙戊酸盐暴露增加了内质网中协助蛋白质折叠的伴侣蛋白的表达，包括GRP78/BiP、GRP94、PDI和钙网蛋白，以及细胞质伴侣蛋白HSP70。然而，在tunicamycin、A23187或葡萄糖胺刺激的HepG2细胞中，丙戊酸暴露于丙戊酸并没有降低内质网应激反应，这表明丙戊酸赋予的保护作用发生在内质网功能障碍的下游。最后，我们证明丙戊酸盐直接抑制糖原合成酶激酶(GSK)-3 α / β。锂是GSK3 α / β的另一种抑制剂，它能够保护细胞免受内质网应激诱导的脂质积累，这表明GSK3在内质网应激的下游信号效应中起着核心作用。保护细胞免受诱发内质网应激的药物/条件的影响的策略可能在治疗与内质网功能障碍相关的越来越多的疾病和失调方面具有潜力。
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 stressinduced 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.