Abstract
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: (1) oxidative stress through a mechanism involving increases in ROS production and MMP-2 protein expression/gelatinolytic activity associated with down-regulation of SOD2 protein; (2) 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; (3) inflammation through enhanced synthesis of proinflammatory cytokines (IL6, IL8 proteins); and (4) 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.
Highlights
Free fatty acids (FFAs) are essential sources of energy within the cells
Oleic Acid but Not Palmitic Acid Increases Neutral Lipid Storage in β Cells To determine whether the metabolic fate of intracellular 250 μM PA differs in the presence of 250 μM OA, we examined neutral lipid accumulation in β cells after 24 h of FFA supplementation
We have found that saturated PA induced the endoplasmic reticulum (ER) stress by proteic expression up-regulation of chaperone BiP, unfolded protein response (UPR) transcription factors, and by PTP1B down-regulation in both mRNA and protein levels
Summary
Free fatty acids (FFAs) are essential sources of energy within the cells. They undergo β-oxidation serving to ATP synthesis into mitochondria. Changes in physiological plasma levels of FFAs are important for regulation of the β cell function (Haber et al, 2006). It has been demonstrated that diminution of the plasma FFA levels in either fasted rats or humans, severely impairs glucose-induced insulin release, but PA can augment insulin release in the presence of non-stimulatory concentrations of glucose (Haber et al, 2006). The FFA excess in β cells generates their dysfunction and death affecting the pancreas by a lipotoxic effect. Intracellular mechanisms of lipotoxicity include the accumulation of diacylglycerol (DAG), increased production of ceramide, reactive oxygen species (ROS) generation, endoplasmic reticulum (ER) stress, inflammation, disturbance of intracellular calcium homeostasis, mitochondrial dysfunction and cell death (Maedler et al, 2001; Listenberger et al, 2003; Beeharry et al, 2004; Welters et al, 2004)
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