Fatty Acid and Lipopolysaccharide Effect on Beta Cells Proteostasis and its Impact on Insulin Secretion
Fatty Acid and Lipopolysaccharide Effect on Beta Cells Proteostasis and its Impact on Insulin Secretion
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DOI：
10.3390/cells8080884
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发表时间：
2019-08-01
期刊：
影响因子：
6
通讯作者：
Garcia-Gonzalez, Victor
中科院分区：
文献类型：
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作者：
Acosta-Montano, Paloma;Rodriguez-Velazquez, Eustolia;Garcia-Gonzalez, Victor
在患有肥胖症和 2 型糖尿病的患者中，经常观察到饱和脂肪酸 (SFA) 的代谢超载（包括 β 细胞功能）和葡萄糖刺激的胰岛素分泌受损。细胞内 Ca2+ 的增加会触发胰岛素颗粒的释放，因此有多种机制可调节 β 细胞内的 Ca2+ 流出，其中包括质膜 Ca2+-ATP 酶 (PMCA)。在这项工作中，我们描述了主要由饱和棕榈酸（PA）（16C）介导的脂毒性与蛋白质稳态（蛋白质稳态）和潜在细胞活力的丧失有关，这种现象是由硬脂酸（18C）、肉豆蔻酸（14C）和月桂酸（12C）在较小程度上诱导的。 PA 定位于内质网，激活未折叠蛋白反应 (UPR) 的臂，脂多糖 (LPS)-内毒素也能促进这种反应。特别是，我们的研究结果表明，PA 和 LPS 引起的 PMCA1/4 表达发生变化，触发 UPR，不仅影响胰岛素释放并导致 β 细胞质量减少，而且还增加活性氮。尽管如此，硬脂酸（SA）并未表现出这些效果。值得注意的是，单不饱和脂肪酸（如油酸和棕榈油酸）的作用避免了 PA 和 LPS 引起的 PMCA1/4 的蛋白水解降解。用 PA/LPS 处理后，油酸恢复了细胞活力，更有趣的是，还缓解了内质网 (ER) 应激。虽然棕榈油酸改善了胰岛素的释放，但这种脂肪酸似乎对细胞内 Ca2+ 调节泵的表达具有更相关的影响。因此，脂肪酸的链长和不饱和度是β细胞蛋白质稳态的决定性因素，从而影响钙和胰岛素分泌的调节。
Metabolic overload by saturated fatty acids (SFA), which comprises beta-cell function, and impaired glucose-stimulated insulin secretion are frequently observed in patients suffering from obesity and type 2 diabetes mellitus. The increase of intracellular Ca2+ triggers insulin granule release, therefore several mechanisms regulate Ca2+ efflux within the beta-cells, among others, the plasma membrane Ca2+-ATPase (PMCA). In this work, we describe that lipotoxicity mediated mainly by the saturated palmitic acid (PA) (16C) is associated with loss of protein homeostasis (proteostasis) and potentially cell viability, a phenomenon that was induced to a lesser extent by stearic (18C), myristic (14C) and lauric (12C) acids. PA was localized on endoplasmic reticulum, activating arms of the unfolded protein response (UPR), as also promoted by lipopolysaccharides (LPS)-endotoxins. In particular, our findings demonstrate an alteration in PMCA1/4 expression caused by PA and LPS which trigger the UPR, affecting not only insulin release and contributing to beta-cell mass reduction, but also increasing reactive nitrogen species. Nonetheless, stearic acid (SA) did not show these effects. Remarkably, the proteolytic degradation of PMCA1/4 prompted by PA and LPS was avoided by the action of monounsaturated fatty acids such as oleic and palmitoleic acid. Oleic acid recovered cell viability after treatment with PA/LPS and, more interestingly, relieved endoplasmic reticulum (ER) stress. While palmitoleic acid improved the insulin release, this fatty acid seems to have more relevant effects upon the expression of regulatory pumps of intracellular Ca2+. Therefore, chain length and unsaturation of fatty acids are determinant cues in proteostasis of beta-cells and, consequently, on the regulation of calcium and insulin secretion.