Gustavo Vazquez-Jimenez J, Chavez-Reyes Jesus, Romero-Garcia Tatiana, Zarain-Herzberg Angel, Valdes-Flores Jesus, Manuel Galindo-Rosales J, Rueda Angelica, Guerrero-Hernandez Agustin, Olivares-Reyes J Alberto
Department of Biochemistry, Center for Research and Advanced Studies of the National Polytechnic Institute, CINVESTAV-IPN, Mexico DF 07360, Mexico.
Department of Biochemistry, School of Medicine, National Autonomous University of Mexico, DF 04510, Mexico.
Cell Signal. 2016 Jan;28(1):53-9. doi: 10.1016/j.cellsig.2015.10.001. Epub 2015 Oct 22.
Palmitic acid is a negative regulator of insulin activity. At the molecular level, palmitic acid reduces insulin stimulated Akt Ser473 phosphorylation. Interestingly, we have found that incubation with palmitic acid of human umbilical vein endothelial cells induced a biphasic effect, an initial transient elevation followed by a sustained reduction of SERCA pump protein levels. However, palmitic acid produced a sustained inhibition of SERCA pump ATPase activity. Insulin resistance state appeared before there was a significant reduction of SERCA2 expression. The mechanism by which palmitic acid impairs insulin signaling may involve endoplasmic reticulum stress, because this fatty acid induced activation of both PERK, an ER stress marker, and JNK, a kinase associated with insulin resistance. None of these effects were observed by incubating HUVEC-CS cells with palmitoleic acid. Importantly, SERCA2 overexpression decreased the palmitic acid-induced insulin resistance state. All these results suggest that SERCA pump might be the target of palmitic acid to induce the insulin resistance state in a human vascular endothelial cell line. Importantly, these data suggest that HUVEC-CS cells respond to palmitic acid-exposure with a compensatory overexpression of SERCA pump within the first hour, which eventually fades out and insulin resistance prevails.
棕榈酸是胰岛素活性的负调节因子。在分子水平上，棕榈酸可降低胰岛素刺激的Akt Ser473磷酸化水平。有趣的是，我们发现用人脐静脉内皮细胞与棕榈酸孵育会产生双相效应，即最初短暂升高，随后SERCA泵蛋白水平持续降低。然而，棕榈酸对SERCA泵ATP酶活性产生持续抑制作用。在SERCA2表达显著降低之前，胰岛素抵抗状态就已出现。棕榈酸损害胰岛素信号传导的机制可能涉及内质网应激，因为这种脂肪酸会诱导内质网应激标志物PERK和与胰岛素抵抗相关的激酶JNK的激活。用棕榈油酸孵育HUVEC-CS细胞未观察到这些效应。重要的是，SERCA2过表达可降低棕榈酸诱导的胰岛素抵抗状态。所有这些结果表明，SERCA泵可能是棕榈酸在人血管内皮细胞系中诱导胰岛素抵抗状态的靶点。重要的是，这些数据表明，HUVEC-CS细胞在最初一小时内会通过SERCA泵的代偿性过表达来应对棕榈酸暴露，最终这种过表达逐渐消失，胰岛素抵抗占主导。
