Fatty Acid and Lipopolysaccharide Effect on Beta Cells Proteostasis and its Impact on Insulin Secretion

Abstract

Metabolic overload by saturated fatty acids (SFA), which comprises β-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 β-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 β-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 β-cells and, consequently, on the regulation of calcium and insulin secretion.

Lipid Modulation in the Formation of β-Sheet Structures. Implications for De Novo Design of Human Islet Amyloid Polypeptide and the Impact on β-Cell Homeostasis

“…BODIPY-Leu probe was synthesized according to protocols developed by our group [22]. Then, the required quantities of l-α-phosphatidylserine and BODIPY-Leu were dissolved in chloroform and mixed vigorously to obtain a clear solution.…”

“…The three branches of UPR are essential in cell homeostasis to reduce ER stress and to ensure adequate synthesis of peptides such as insulin [20]. Indeed, in several reports, we have described the effect of metabolic overload on the dysregulation of UPR arms [21,22].…”

“…Several reports suggest that the C-native segment of IAPP (residues 23-37) is a critical domain in the structural transitions that trigger amyloid formation [6], hence, it could be a target for the development of strategies to reduce aggregation. Based on multiple sequence alignment among Nand C-domains on 240 sequences of different species, the N-domain (residues 1-20) has been described as a conserved sequence among a wide variety of organisms, while the C-domain (residues [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] has been restricted to phylogenetically close groups [7]. Therefore, we proposed a panel of optimized IAPP sequences, which could reduce aggregation with only one residue substitution [7].…”

“…Given this situation, the initial events of misfolding and amyloid aggregation promote a cascade of pathological processes considered the hallmark in the progression of several chronic degenerative diseases [8][9][10][11][12][13] that might be associated with conditions related to metabolic overload [21,22]. Having this in mind, we herein characterized the role of lipid systems on the conformational transitions of the most aggregative C-terminal domain of hIAPP, and through a biomimetic approach, evaluated this condition on variants F 23 R and I 26 A that potentially could reduce aggregation.…”

Target lipidomics reveals associations between serum sphingolipids and insulin sensitivity by the glucose clamp

“…A previous study based on the OGTT observed an association between higher total fasting plasma FFA levels and lower insulin secretion in children and adults without adjustments for confounding factors (32). Some studies proved that chronic FFA-induced lipotoxicity on pancreatic islets contributed to β cell dysfunction (33,34). Therefore, a reduction in elevated plasma FFA levels might be a critical therapeutic target for obesity-related type 2 diabetes.…”