Nemecz Miruna, Constantin Alina, Dumitrescu Madalina, Alexandru Nicoleta, Filippi Alexandru, Tanko Gabriela, Georgescu Adriana
Department of Pathophysiology and Pharmacology, Institute of Cellular Biology and Pathology 'Nicolae Simionescu' of Romanian Academy, Bucharest, Romania.
Front Pharmacol. 2019 Jan 21;9:1554. doi: 10.3389/fphar.2018.01554. eCollection 2018.
In this study, we aimed to identify the mechanisms underlying the different effects of palmitic acid and oleic acid on human pancreatic beta cell function. To address this problem, the oxidative stress, endoplasmic reticulum stress, inflammation, apoptosis and their mediator molecules have been investigated in the insulin releasing beta cells exposed to palmitic and/or oleic acid. Herein, we have demonstrated that in cultured 1.1B4 beta cells oleic acid promotes neutral lipid accumulation and insulin secretion, whereas palmitic acid is poorly incorporated into triglyceride and it does not stimulate insulin secretion from human pancreatic islets at physiologically glucose concentrations. In addition, palmitic acid caused: oxidative stress through a mechanism involving increases in ROS production and MMP-2 protein expression/gelatinolytic activity associated with down-regulation of SOD2 protein; endoplasmic reticulum stress by up-regulation of chaperone BiP protein and unfolded protein response (UPR) transcription factors (eIF2α, ATF6, XBP1u proteins) and by PTP-1B down-regulation in both mRNA and protein levels; inflammation through enhanced synthesis of proinflammatory cytokines (IL6, IL8 proteins); and apoptosis by enforced proteic expression of CHOP multifunctional transcription factor. Oleic acid alone had opposite effects due to its different capacity of controlling these metabolic pathways, in particular by reduction of the ROS levels and MMP-2 activity, down-regulation of BiP, eIF2α, ATF6, XBP1u, CHOP, IL6, IL8 and by SOD2 and PTP-1B overexpression. The supplementation of saturated palmitic acid with the monounsaturated oleic acid reversed the negative effects of palmitic acid alone regulating insulin secretion from pancreatic beta cells through ROS, MMP-2, ATF6, XBP1u, IL8 reduction and SOD2, PTP-1B activation. Our findings have shown the protective action of oleic acid against palmitic acid on beta cell lipotoxicity through promotion of triglyceride accumulation and insulin secretion and regulation of some effector molecules involved in oxidative stress, endoplasmic reticulum stress, inflammation and apoptosis.
在本研究中，我们旨在确定棕榈酸和油酸对人胰腺β细胞功能产生不同影响的潜在机制。为解决这一问题，我们对暴露于棕榈酸和/或油酸的胰岛素释放β细胞中的氧化应激、内质网应激、炎症、凋亡及其介导分子进行了研究。在此，我们证明，在培养的1.1B4β细胞中，油酸促进中性脂质积累和胰岛素分泌，而棕榈酸很少掺入甘油三酯，并且在生理葡萄糖浓度下不刺激人胰岛分泌胰岛素。此外，棕榈酸通过以下机制导致：氧化应激，其机制涉及活性氧生成增加以及与超氧化物歧化酶2（SOD2）蛋白下调相关的基质金属蛋白酶2（MMP-2）蛋白表达/明胶酶活性增加；内质网应激，通过伴侣蛋白BiP蛋白上调以及未折叠蛋白反应（UPR）转录因子（真核翻译起始因子2α（eIF2α）、活化转录因子6（ATF6）、未剪接的X盒结合蛋白1（XBP1u）蛋白）上调，以及蛋白酪氨酸磷酸酶1B（PTP-1B）在mRNA和蛋白水平的下调；炎症，通过促炎细胞因子（白细胞介素6（IL6）、白细胞介素8（IL8）蛋白）合成增强；以及凋亡，通过多功能转录因子C/EBP同源蛋白（CHOP）的蛋白表达增强。单独的油酸由于其控制这些代谢途径的能力不同而具有相反的作用，特别是通过降低活性氧水平和MMP-2活性、下调BiP、eIF2α、ATF6、XBP1u、CHOP、IL6、IL8以及过表达SOD2和PTP-1B。用单不饱和油酸补充饱和棕榈酸可逆转棕榈酸单独作用时对胰腺β细胞胰岛素分泌的负面影响，通过降低活性氧、MMP-2、ATF6、XBP1u、IL8以及激活SOD2和PTP-1B来调节胰岛素分泌。我们的研究结果表明，油酸通过促进甘油三酯积累和胰岛素分泌以及调节参与氧化应激、内质网应激、炎症和凋亡的一些效应分子，对棕榈酸诱导的β细胞脂毒性具有保护作用。
