Disruption of endoplasmic reticulum structure and integrity in lipotoxic cell death
Disruption of endoplasmic reticulum structure and integrity in lipotoxic cell death
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DOI：
10.1194/jlr.m600299-jlr200
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发表时间：
2006-12-01
影响因子：
6.5
通讯作者：
Schaffer, Jean E.
中科院分区：
文献类型：
--
作者：
Borradaile, Nica M.;Han, Xianlin;Schaffer, Jean E.
非脂肪组织中脂质积聚或脂毒性诱导的细胞功能障碍和死亡可能导致肥胖和2型糖尿病的发病机制。然而，导致脂毒性细胞死亡的机制知之甚少。我们最近报道，在中国仓鼠卵巢（CHO）细胞和H9 C2成心肌细胞，脂质过负荷诱导孵育与500 μ M棕榈酸导致细胞内积累的活性氧，随后诱导内质网（ER）的压力和细胞死亡。在这里，我们表明，棕榈酸也损害ER功能，通过更直接的机制。在CHO细胞的微粒体膜中，棕榈酸酯迅速掺入饱和磷脂和甘油三酯物质中。由此产生的膜重塑与ER的急剧扩张和蛋白质折叠分子伴侣在5小时内重新分配到胞质溶胶，表明ER膜的完整性受损。增加β-氧化，通过激活AMP-活化蛋白激酶，减少棕榈酸掺入微粒体，减少逃逸的分子伴侣的胞质溶胶，并减少随后的半胱天冬酶激活和细胞死亡。因此，棕榈酸酯迅速增加了ER的饱和脂质含量，导致ER形态和完整性受损，表明该细胞器的结构和功能受损参与了对脂肪酸过载的细胞反应。
Cell dysfunction and death induced by lipid accumulation in nonadipose tissues, or lipotoxicity, may contribute to the pathogenesis of obesity and type 2 diabetes. However, the mechanisms leading to lipotoxic cell death are poorly understood. We recently reported that, in Chinese hamster ovary (CHO) cells and in H9c2 cardiomyoblasts, lipid overload induced by incubation with 500 mu M palmitate leads to intracellular accumulation of reactive oxygen species, which subsequently induce endoplasmic reticulum ( ER) stress and cell death. Here, we show that palmitate also impairs ER function through a more direct mechanism. Palmitate was rapidly incorporated into saturated phospholipid and triglyceride species in microsomal membranes of CHO cells. The resulting membrane remodeling was associated with dramatic dilatation of the ER and redistribution of protein-folding chaperones to the cytosol within 5 h, indicating compromised ER membrane integrity. Increasing beta-oxidation, through the activation of AMP-activated protein kinase, decreased palmitate incorporation into microsomes, decreased the escape of chaperones to the cytosol, and decreased subsequent caspase activation and cell death. Thus, palmitate rapidly increases the saturated lipid content of the ER, leading to compromised ER morphology and integrity, suggesting that impairment of the structure and function of this organelle is involved in the cellular response to fatty acid overload.