The Natural Protective Mechanism Against Hyperglycemia in Vascular Endothelial Cells

Riahi, Yael; Sin-Malia, Yoav; Cohen, Guy; Alpert, Evgenia; Gruzman, Arie; Eckel, Jürgen; Staels, Bart; Guichardant, Michel; Sasson, Shlomo

doi:10.2337/db09-1207

Cited by 66 publications

(75 citation statements)

References 40 publications

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“…Being saturated, PA is not subjected to peroxidation, yet it effectively augmented 4-HNE production in INS-1E cells by increasing the availability of AA and LA to peroxidation. We, and others, have reported that 4-hydroxyalkenals activate the PPARδ nuclear receptor in various cells, including beta cells [13,19,24,35,38]. The findings that 4-HNE scavenging with L-carnosine and PPARδ inhibition or its silencing attenuated PA-induced GSIS further support the role of the 4-HNE-PPARδ axis in beta cell function [13,39].…”

Section: Discussionsupporting

confidence: 59%

“…PPARδ-luciferase reporter assay Subconfluent INS-1E cultures were co-transfected with the hPPARδ expression vector along with the hRXR-, green fluorescent protein (GFP)-and Renilla luciferase expression vectors and the 3XPPRE-TK-luciferase reporter, as described [19]. The yield of the transfection, assessed by GFP fluorescence, was >85%.…”

Section: Fatty Acid-based Lipidomic Analysismentioning

confidence: 99%

“…Western blot and dot blot analyses Cell lysates were prepared as described [19] and used for western blot analyses of PPARδ, p-Thr 980 -protein kinase RNA-like ER kinase (PERK), p-Ser 724 -inositol-requiring enzyme-1 (IRE), total IRE and α-tubulin, according to the suppliers' protocols. Dot blot analysis was used to detect 4-HNE-histidine protein adducts.…”

Section: Fatty Acid-based Lipidomic Analysismentioning

confidence: 99%

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Beta cell response to nutrient overload involves phospholipid remodelling and lipid peroxidation

et al. 2015

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Aims/hypothesis Membrane phospholipids are the major intracellular source for fatty acid-derived mediators, which regulate myriad cell functions. We showed previously that high glucose levels triggered the hydrolysis of polyunsaturated fatty acids from beta cell phospholipids. These fatty acids were subjected to free radical-catalysed peroxidation to generate the bioactive aldehyde 4-hydroxy-2E-nonenal (4-HNE). The latter activated the nuclear peroxisome proliferator-activated receptor-δ (PPARδ), which in turn augmented glucosestimulated insulin secretion. The present study aimed at investigating the combined effects of glucose and fatty acid overload on phospholipid turnover and the subsequent generation of lipid mediators, which affect insulin secretion and beta cell viability. Methods INS-1E cells were incubated with increasing glucose concentrations (5-25 mmol/l) without or with palmitic acid (PA; 50-500 μmol/l) and taken for fatty acid-based lipidomic analysis and functional assays. Rat isolated islets of Langerhans were used similarly. Results PA was incorporated into membrane phospholipids in a concentration-and time-dependent manner; incorporation was highest at 25 mmol/l glucose. This was coupled to a rapid exchange with saturated, mono-unsaturated and polyunsaturated fatty acids. Importantly, released arachidonic acid and linoleic acid were subjected to peroxidation, resulting in the generation of 4-HNE, which further augmented insulin secretion by activating PPARδ in beta cells. However, this adaptive increase in insulin secretion was abolished at high glucose and PA levels, which induced endoplasmic reticulum stress, apoptosis and cell death. Conclusions/interpretation These findings highlight a key role for phospholipid remodelling and fatty acid peroxidation in mediating adaptive and cytotoxic interactions induced by nutrient overload in beta cells.

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Section: Discussionsupporting

confidence: 59%

Section: Fatty Acid-based Lipidomic Analysismentioning

confidence: 99%

Section: Fatty Acid-based Lipidomic Analysismentioning

confidence: 99%

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Beta cell response to nutrient overload involves phospholipid remodelling and lipid peroxidation

et al. 2015

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“…The authors associate the findings to arachidonic acid metabolites, products of lipid peroxidation and calreticulin-induced destabilization of GLUT1 mRNA, rendering it susceptible to degradation. Consequently, the cell content of GLUT1 protein and its abundance at the PM are reduced, resulting in downregulation of glucose uptake (47). These studies seem to indicate an entirely different mechanism that involves ROS-induced lipid peroxidation and generation of a second messenger that activates peroxisome proliferator-activated receptor-␦.…”

Section: Discussionmentioning

confidence: 87%

Reactive oxygen species downregulate glucose transport system in retinal endothelial cells

Fernandes

Hosoya

Pereira³

2011

American Journal of Physiology-Cell Physiology

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Fernandes R, Hosoya K, Pereira P. Reactive oxygen species downregulate glucose transport system in retinal endothelial cells. Am J Physiol Cell Physiol 300: C927-C936, 2011. First published January 12, 2011; doi:10.1152/ajpcell.00140.2010.-Retinal endothelial cells are believed to play an important role in the pathogenesis of diabetic retinopathy. In previous studies, we and others demonstrated that glucose transporter 1 (GLUT1) is downregulated in response to hyperglycemia. Increased oxidative stress is likely to be the event whereby hyperglycemia is transduced into endothelial cell damage. However, the effects of sustained oxidative stress on GLUT1 regulation are not clearly established. The objective of this study is to evaluate the effect of increased oxidative stress on glucose transport and on GLUT1 subcellular distribution in a retinal endothelial cell line and to elucidate the signaling pathways associated with such regulation. Conditionally immortalized rat retinal endothelial cells (TRiBRB) were incubated with glucose oxidase, which increases the intracellular hydrogen peroxide levels, and GLUT1 regulation was investigated. The data showed that oxidative stress did not alter the total levels of GLUT1 protein, although the levels of mRNA were decreased, and there was a subcellular redistribution of GLUT1, decreasing its content at the plasma membrane. Consistently, the half-life of the protein at the plasma membrane markedly decreased under oxidative stress. The proteasome appears to be involved in GLUT1 regulation in response to oxidative stress, as revealed by an increase in stabilization of the protein present at the plasma membrane and normalization of glucose transport following proteasome inhibition. Indeed, levels of ubiquitinated GLUT1 increase as revealed by immunoprecipitation assays. Furthermore, data indicate that protein kinase B activation is involved in the stabilization of GLUT1 at the plasma membrane. Thus subcellular redistribution of GLUT1 under conditions of oxidative stress is likely to contribute to the disruption of glucose homeostasis in diabetes.glucose transporter 1; oxidative stress; protein kinase B; proteasome; retinal endothelial cells; reactive oxygen species REACTIVE OXYGEN SPECIES (ROS) such as hydrogen peroxide (H 2 O 2 ) and superoxide anion are constantly produced intracellularly as a result of normal metabolic activity.

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“…The principles have mostly commonly been explored with linoleic acid and have focused on the formation of 4-hydroxy-2-nonenal (HNE), owing to the fact that it is one of the most abundantly formed lipid peroxidation products and has interesting biological effects [8,28,29]. The mechanisms are (i) reduction of hydroperoxide to an alkoxyl radical in the presence of a transition metal followed by β-scission; (ii) Hock rearrangement of a hydroperoxide and migration of a C-C to a C-O bond and cleavage; (iii) cyclization to form a dioxetane and subsequent cleavage.…”

Section: Aldehydes Are Fragmentation Products Of Oxidized Lipidsmentioning

confidence: 99%

Chemistry and analysis of HNE and other prominent carbonyl-containing lipid oxidation compounds

Sousa

Pitt

Spickett

2017

Free Radical Biology and Medicine

145

105

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The process of lipid oxidation generates a diverse array of small aldehydes and carbonyl-containing compounds, which may occur in free form or esterified within phospholipids and cholesterol esters. These aldehydes mostly result from fragmentation of fatty acyl chains following radical oxidation, and the products can be subdivided into alkanals, alkenals (usually D,β-unsaturated), γ-substituted alkenals and bis-aldehydes.Isolevuglandins are non-fragmented di-carbonyl compounds derived from H 2 -isoprostanes, and oxidation of the ω-3-fatty acid docosahexenoic acid yield analogous 22 carbon neuroketals. Non-radical oxidation by hypochlorous acid can generate D-chlorofatty aldehydes from plasmenyl phospholipids. Most of these compounds are reactive and have generally been considered as toxic products of a deleterious process. The reactivity is especially high for the D,β-unsaturated alkenals, such as acrolein and crotonaldehyde, and for γ-substituted alkenals, of which 4-hydroxy-2-nonenal and 4-oxo-2-nonenal are best Page | 2 known. Nevertheless, in recent years several previously neglected aldehydes have been investigated and also found to have significant reactivity and biological effects; notable examples are 4-hydroxy-2-hexenal and 4-hydroxy-dodecadienal. This has led to substantial interest in the biological effects of all of these lipid oxidation products and their roles in disease, including proposals that HNE is a second messenger or signalling molecule.However, it is becoming clear that many of the effects elicited by these compounds relate to their propensity for forming adducts with nucleophilic groups on proteins, DNA and specific phospholipids. This emphasizes the need for good analytical methods, not just for free lipid oxidation products but also for the resulting adducts with biomolecules. The most informative methods are those utilizing HPLC separations and mass spectrometry, although analysis of the wide variety of possible adducts is very challenging. Nevertheless, evidence for the occurrence of lipid-derived aldehyde adducts in biological and clinical samples is building, and offers an exciting area of future research. AbbreviationsAcr-dG, 1,N2-propanodeoxyguanosine; AGEs, advanced glycation end-product; ALEs, advanced lipoxidation end product; ApoB100, apolipoprotein B100; ApoE, apolipoprotein E; ARP, aldehyde reactive probe; AspN, endoproteinase AspN (flavastacin); βLG, β-lactoglobulin; BHZ, biotin hydrazide; BN-PAGE, blue native polyacrylamide gel

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The Natural Protective Mechanism Against Hyperglycemia in Vascular Endothelial Cells

Cited by 66 publications

References 40 publications

Beta cell response to nutrient overload involves phospholipid remodelling and lipid peroxidation

Beta cell response to nutrient overload involves phospholipid remodelling and lipid peroxidation

Reactive oxygen species downregulate glucose transport system in retinal endothelial cells

Chemistry and analysis of HNE and other prominent carbonyl-containing lipid oxidation compounds

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