Evidence for in situ ethanolamine phospholipid adducts with hydroxy-alkenals

Bacot, Sandrine; Bernoud-Hubac, Nathalie; Chantegrel, Bernard; Deshayes, Christian; Doutheau, Alain; Ponsin, Gabriel; Lagarde, Michel; Guichardant, Michel

doi:10.1194/jlr.m600340-jlr200

Cited by 66 publications

(48 citation statements)

References 22 publications

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“…Furthermore, inhibition of ER stress blocks acrolein-induced increases in mRNA levels of the proinflammatory cytokines TNF␣, IL-6, and IL-8 (33). As ␥KA, HNE, and acrolein all modify PE (8,11,13,(15)(16)(17)(18), our finding that ␥KA-PE induces CHOP, IL-8, and MCP-1 expression raises the possibility that these other aldehydes also mediate their inflammatory effects by forming modified PE, which induce ER stress responses.…”

Section: Discussionmentioning

confidence: 99%

Phosphatidylethanolamines Modified by γ-Ketoaldehyde (γKA) Induce Endoplasmic Reticulum Stress and Endothelial Activation

Guo

Chen²,

Cox³

et al. 2011

Journal of Biological Chemistry

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Peroxidation of plasma lipoproteins has been implicated in the endothelial cell activation and monocyte adhesion that initiate atherosclerosis, but the exact mechanisms underlying this activation remain unclear. Lipid peroxidation generates lipid aldehydes, including the ␥-ketoaldehydes (␥KA), also termed isoketals or isolevuglandins, that readily modify the amine headgroup of phosphatidylethanolamine (PE). We hypothesized that aldehyde modification of PE could mediate some of the proinflammatory effects of lipid peroxidation. We found that PE modified by ␥KA (␥KA-PE) induced THP-1 monocyte adhesion to human umbilical cord endothelial cells. ␥KA-PE also induced expression of adhesion molecules and increased MCP-1 and IL-8 mRNA in human umbilical cord endothelial cells. To determine the structural requirements for ␥KA-PE activity, we tested several related compounds. PE modified by 4-oxo-pentanal induced THP-1 adhesion, but N-glutaroyl-PE and C 18:0 N-acyl-PE did not, suggesting that an N-pyrrole moiety was essential for cellular activity. As the N-pyrrole headgroup might distort the membrane, we tested the effect of the pyrrolePEs on membrane parameters. ␥KA-PE and 4-oxo-pentanal significantly reduced the temperature for the liquid crystalline to hexagonal phase transition in artificial bilayers, suggesting that these pyrrole-PE markedly altered membrane curvature. Additionally, fluorescently labeled ␥KA-PE rapidly internalized to the endoplasmic reticulum (ER); ␥KA-PE induced C/EBP homologous protein CHOP and BiP expression and p38 MAPK activity, and inhibitors of ER stress reduced ␥KA-PE-induced C/EBP homologous protein CHOP and BiP expression as well as EC activation, consistent with ␥KA-PE inducing ER stress responses that have been previously linked to inflammatory chemokine expression. Thus, ␥KA-PE is a potential mediator of the inflammation induced by lipid peroxidation.Lipid peroxidation has been implicated in a host of pathological processes, including inflammation and atherosclerosis, but there is still much that is unknown about the mechanisms linking lipid peroxidation to the activation of inflammatory responses. Lipid peroxidation produces a plethora of lipid aldehydes ( Fig. 1), including malondialdehyde, acrolein, and 4-hydroxynonenal (HNE).3 It also produces a large family of ␥-ketoaldehydes (␥KA), regioisomers that have been given the trivial name of isoketals or isolevuglandins. Exposure of vascular cells to various aldehydes results in endothelial dysfunction, secretion of cytokines, and recruitment of monocytes (1-7), all of which are key steps in the initiation of the chronic inflammatory conditions leading to atherosclerosis.Despite these potentially important inflammatory effects, the mechanisms whereby lipid aldehydes induce their effects on vascular cells are still poorly understood. Significant effort has focused on the effects of protein and DNA modification by lipid aldehydes. However, recent studies have shown that lipid aldehydes, including malondialdehyde, acrolein, HNE, and ␥KA, a...

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Section: Discussionmentioning

confidence: 99%

Phosphatidylethanolamines Modified by γ-Ketoaldehyde (γKA) Induce Endoplasmic Reticulum Stress and Endothelial Activation

Guo

Chen²,

Cox³

et al. 2011

Journal of Biological Chemistry

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“…Since lipid aldehydes are rather long-lived, they can reach and attack targets such as phospholipids, DNA, and proteins distant from their original site of formation (3,17,40,52).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of glutathione peroxidase 4 prevents β-cell dysfunction induced by prolonged elevation of lipids in vivo

Koulajian

Ivovic

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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-We have shown that oxidative stress is a mechanism of free fatty acid (FFA)-induced ␤-cell dysfunction. Unsaturated fatty acids in membranes, including plasma and mitochondrial membranes, are substrates for lipid peroxidation, and lipid peroxidation products are known to cause impaired insulin secretion. Therefore, we hypothesized that mice overexpressing glutathione peroxidase-4 (GPx4), an enzyme that specifically reduces lipid peroxides, are protected from fat-induced ␤-cell dysfunction. GPx4-overexpressing mice and their wild-type littermate controls were infused intravenously with saline or oleate for 48 h, after which reactive oxygen species (ROS) were imaged, using dihydrodichlorofluorescein diacetate in isolated islets, and ␤-cell function was assessed ex vivo in isolated islets and in vivo during hyperglycemic clamps. Forty-eight-hour FFA elevation in wild-type mice increased ROS and the lipid peroxidation product malondialdehyde and impaired ␤-cell function ex vivo in isolated islets and in vivo, as assessed by decreased disposition index. Also, islets of wild-type mice exposed to oleate for 48 h had increased ROS and lipid peroxides and decreased ␤-cell function. In contrast, GPx4-overexpressing mice showed no FFA-induced increase in ROS and lipid peroxidation and were protected from the FFA-induced impairment of ␤-cell function assessed in vitro, ex vivo and in vivo. These results implicate lipid peroxidation in FFA-induced ␤-cell dysfunction. oxidative stress; lipid peroxide; glutathione peroxidase 4; lipotoxicity; ␤-cell dysfunction; in vivo CHRONIC EXPOSURE of pancreatic ␤-cells to free fatty acids (FFA) impairs ␤-cell function (21). Although not all studies are concordant (45), a growing body of evidence implicates oxidative stress as a mechanism of FFA-induced ␤-cell dysfunction (9,38,46,60,67). Pancreatic ␤-cells have low antioxidant defenses (34) and are thus susceptible to reactive oxygen species (ROS)-induced decrease in function and viability (37,47). We have demonstrated previously that 1) prolonged elevation of plasma FFA in rats impairs glucose-stimulated insulin secretion (GSIS) in vivo during hyperglycemic clamps and ex vivo in freshly isolated islets and 2) the treatment with the antioxidants N-acetylcysteine, taurine, or tempol, which decreases islet ROS measured with dihydrodichlorofluorescein diacetate (H 2 DCF-DA), prevents the impairing effects of FFA on ␤-cell function (51). Zhang et al. (72) confirmed our findings in rats (51) in a different model of prolonged FFA elevation. Our group has also shown that the antioxidant taurine alleviates FFA-induced impairment in ␤-cell function in humans (68).The type and cellular localization of ROS in FFA-induced ␤-cell dysfunction are still unclear. We have demonstrated that cytosolic superoxide plays a causal role in fat-induced ␤-cell dysfunction (32); however, since the antioxidants N-acetylcysteine and taurine, which do not decrease superoxide, were also effective in restoring ␤-cell function (51), other ROS are implicated in addition ...

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“…In addition to being markers of lipid peroxidation in vivo, 4-HNE and 4-HHE induce noxious effects on biological systems. These lipid aldehydes are prone to react with thiol and amine moieties and produce Schiff base and/or Michael adducts with biomole cules, such as proteins, DNA, and phospholipids ( 12,13 ). Numerous studies reported the genotoxicity and cytotoxicity of these 4-hydroxy-2-alkenals on tissues and cells in pathophysiological contexts (14)(15)(16), but nothing is known to date about the possible contribution of 4-hydroxy-2-alkenals present in food products, their fate after ingestion, and their metabolic effects.…”

Section: Caco-2/tc7 Cell Culture and Treatmentmentioning

confidence: 99%

Dietary oxidized n-3 PUFA induce oxidative stress and inflammation: role of intestinal absorption of 4-HHE and reactivity in intestinal cells

Awada

Soulage

Meynier

et al. 2012

Journal of Lipid Research

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Evidence for in situ ethanolamine phospholipid adducts with hydroxy-alkenals

Cited by 66 publications

References 22 publications

Phosphatidylethanolamines Modified by γ-Ketoaldehyde (γKA) Induce Endoplasmic Reticulum Stress and Endothelial Activation

Phosphatidylethanolamines Modified by γ-Ketoaldehyde (γKA) Induce Endoplasmic Reticulum Stress and Endothelial Activation

Overexpression of glutathione peroxidase 4 prevents β-cell dysfunction induced by prolonged elevation of lipids in vivo

Dietary oxidized n-3 PUFA induce oxidative stress and inflammation: role of intestinal absorption of 4-HHE and reactivity in intestinal cells

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