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Polyunsaturated fatty acid enrichment enhances endothelial cell-induced low-density-lipoprotein peroxidation.

ABSTRACT: Oxidative modification of low-density lipoprotein (LDL) is an important feature in the initiation and progression of atherosclerosis. LDL modification by endothelial cells was studied after supplementation of the cells with oleic acid and polyunsaturated fatty acids (PUFA) of the n-6 and n-3 series. In terms of the lipid peroxidation product [thiobarbituric acid reactive substances (TBARS)] content and diene level of the LDL particle, oleic acid had no significant effect, and linoleic acid was poorly effective. Gamma linolenic acid (C18:3,n-6) and arachidonic acid (C20:4,n-6) increased by about 1.6-1.9-fold the cell-mediated LDL modification. PUFA from the n-3 series, alpha linolenic acid (C18:3,n-3), eicosapentaenoic acid (C20:5,n-3) and docosahexaenoic acid (C22:6,n-3), induced a less marked effect (1. 3-1.6-fold increase). The relative electrophoretic mobility of the LDL particle and its degradation by macrophages were enhanced in parallel. Concomitantly, PUFA stimulated superoxide anion secretion by endothelial cells. The intracellular TBARS content was also increased by PUFA. Comparison of PUFA from the two series indicates a good correlation between LDL oxidative modification, superoxide anion secretion and intracellular lipid peroxidation. The lipophilic antioxidant vitamin E decreased the basal as well as the PUFA-stimulated LDL peroxidation. These results indicate that PUFAs with a high degree of unsaturation of the n-6 and n-3 series could accelerate cell-mediated LDL peroxidation and thus aggravate the atherosclerotic process.

SUBMITTER: Maziere C

PROVIDER: S-EPMC1219841 | biostudies-other | 1998 Nov

REPOSITORIES: biostudies-other

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Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis.

Project description:Ferroptosis is form of regulated nonapoptotic cell death that is involved in diverse disease contexts. Small molecules that inhibit glutathione peroxidase 4 (GPX4), a phospholipid peroxidase, cause lethal accumulation of lipid peroxides and induce ferroptotic cell death. Although ferroptosis has been suggested to involve accumulation of reactive oxygen species (ROS) in lipid environments, the mediators and substrates of ROS generation and the pharmacological mechanism of GPX4 inhibition that generates ROS in lipid environments are unknown. We report here the mechanism of lipid peroxidation during ferroptosis, which involves phosphorylase kinase G2 (PHKG2) regulation of iron availability to lipoxygenase enzymes, which in turn drive ferroptosis through peroxidation of polyunsaturated fatty acids (PUFAs) at the bis-allylic position; indeed, pretreating cells with PUFAs containing the heavy hydrogen isotope deuterium at the site of peroxidation (D-PUFA) prevented PUFA oxidation and blocked ferroptosis. We further found that ferroptosis inducers inhibit GPX4 by covalently targeting the active site selenocysteine, leading to accumulation of PUFA hydroperoxides. In summary, we found that PUFA oxidation by lipoxygenases via a PHKG2-dependent iron pool is necessary for ferroptosis and that the covalent inhibition of the catalytic selenocysteine in Gpx4 prevents elimination of PUFA hydroperoxides; these findings suggest new strategies for controlling ferroptosis in diverse contexts.

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Low-density lipoprotein receptor-5 contributes to whole body metabolism by regulating fatty acid metabolism in the osteoblast

Project description:Wnt signaling is critical for normal skeletal development as well as whole-body metabolic function. In this study, we described a previously unrecognized function for Wnt-Lrp5 signaling in the osteoblast that allows bone to acquire the resources necessary to fuel bone formation. Mice lacking the Lrp5 co-receptor specifically in osteoblasts and osteocytes exhibit the expected reductions in postnatal bone mass and also develop peripheral adiposity with corresponding reductions in energy expenditure. Conversely, mice expressing a high-bone mass mutant Lrp5 allele are leaner with reduced plasma triglyceride and free fatty acid levels. In this context, Wnt-initiated signals downstream of Lrp5, but not Lrp6, regulate the expression of key enzymes required for fatty acid β-oxidation. These results suggest that Wnt-Lrp5 signaling regulates basic cellular activities beyond those associated with fate-specification and differentiation in bone and that the skeleton influences global energy homeostasis via mechanisms independent of osteocalcin and glucose metabolism Total RNA isolated from cultures of Lrp5-deficient osteoblasts differentiated for 7 days in vitro compared to control osteoblasts

2014-03-14 | E-GEOD-55900 | biostudies-arrayexpress

Low-density lipoprotein receptor-5 contributes to whole body metabolism by regulating fatty acid metabolism in the osteoblast

2014-03-14 | GSE55900 | GEO

FAF1 blocks ferroptosis by inhibiting peroxidation of polyunsaturated fatty acids.

Project description:Iron-dependent peroxidation of polyunsaturated fatty acids (PUFAs) leads to ferroptosis. While detoxification reactions removing lipid peroxides in phospholipids such as that catalyzed by glutathione peroxidase 4 (GPX4) protect cells from ferroptosis, the mechanism through which cells prevent PUFA peroxidation was not completely understood. We previously identified Fas-associated factor 1 (FAF1) as a protein directly interacting with free PUFAs through its UAS domain. Here we report that this interaction is crucial to protect cells from ferroptosis. In the absence of FAF1, cultured cells became sensitive to ferroptosis upon exposure to physiological levels of PUFAs, and mice developed hepatic injury upon consuming a diet enriched in PUFA. Mechanistically, we demonstrate that FAF1 assembles a globular structure that sequesters free PUFAs into a hydrophobic core, a reaction that prevents PUFA peroxidation by limiting its access to iron. Our study suggests that peroxidation of free PUFAs contributes to ferroptosis, and FAF1 acts upstream of GPX4 to prevents initiation of ferroptosis by limiting peroxidation of free PUFAs.

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Gene-diet interactions with polymorphisms of the MGLL gene on plasma low-density lipoprotein cholesterol and size following an omega-3 polyunsaturated fatty acid supplementation: a clinical trial.

Project description:Omega-3 (n-3) polyunsaturated fatty acid (PUFA) consumption increases low-density lipoprotein (LDL) cholesterol (C) concentrations and particle size. Studies showed that individuals with large, buoyant LDL particles have decreased risk of cardiovascular diseases. However, a large inter-individual variability is observed in LDL particle size. Genetic factors may explain the variability of LDL-C concentrations and particle size after an n-3 PUFA supplementation. The monoglyceride lipase (MGLL) enzyme, encoded by the MGLL gene, plays an important role in lipid metabolism, especially lipoprotein metabolism. The aim of this study was to investigate if polymorphisms (SNPs) of the MGLL gene influence the variability of LDL-C and LDL particle size in response to an n-3 PUFA supplementation.210 subjects completed the study. They consumed 5 g/d of a fish oil supplement (1.9-2.2 g eicosapentaenoic acid and 1.1 g docosaexaenoic acid) during 6 weeks. Plasma lipids were measured before and after the supplementation period and 18 SNPs of the MGLL gene, covering 100% of common genetic variations (minor allele frequency ?0.05), have been genotyped using TaqMan technology (Life Technologies Inc., Burlington, ON, CA).Following the n-3 PUFA supplementation, 55% of subjects increased their LDL-C levels. In a model including the supplementation, genotype and supplementation*genotype effects, gene-diet interaction effects on LDL-C concentrations (rs782440, rs6776142, rs555183, rs6780384, rs6787155 and rs1466571) and LDL particle size (rs9877819 and rs13076593) were observed for the MGLL gene SNPs (p?<?0.05).SNPs within the MGLL gene may modulate plasma LDL-C levels and particle size following an n-3 PUFA supplementation. This trial was registered at clinicaltrials.gov as NCT01343342.

| S-EPMC4040477 | biostudies-literature

Fatty acid synthesis suppresses dietary polyunsaturated fatty acid use

Project description:Metabolic diseases are closely linked to aberrant synthesis of endogenous fatty acids in the liver, called de novo lipogenesis (DNL), which is mediated by the enzyme fatty acid synthase (FASN). The composition of complex lipids consists of saturated or monosaturated fatty acids, which can be endogenously produced, and polyunsaturated fatty acids (PUFA), which are strictly dietary. Compositional differences between individuals are insufficiently understood and may influence the onset and progression of metabolic and cardiovascular diseases. Here we show that DNL critically determines the use of dietary PUFA. A patient with a hypofunctional heterozygous de novo Arg2177Cys variant in FASN exhibited an elevated composition of PUFA, which was phenocopied by pharmacological inhibition of FASN with TVB-2640 in patients with nonalcoholic steatohepatitis (NASH). In mice, the incorporation rate of supplemented omega-3 PUFA during an obesogenic diet was increased by genetic or pharmacologic reduction of DNL. Mechanistically, we show that the FASN variant exhibited a cysteine-dependent, non-enzymatic acetylation of FASN, which resulted in hyperubiquitinylation and decreased protein stability. Our study further reveals that PUFA storage is an active, enzymatic process controlled by FASN, diacylglycerol O-acyltransferase 2 (DGAT2) and MFSD2A, a membrane-transport protein, and that combining FASN inhibition and PUFA supplementation exerts additive beneficial metabolic effects. These findings provide evidence that the success of PUFA supplementation may depend on the rate of endogenous DNL and that combined PUFA supplementation and FASN inhibition may be a promising approach targeting metabolic disease.

2023-12-19 | PXD045908 | Pride

Peroxisome proliferator-activated receptor delta promotes very low-density lipoprotein-derived fatty acid catabolism in the macrophage.

Project description:Significant attention has focused on the role of low-density lipoprotein (LDL) in the pathogenesis of atherosclerosis. However, recent advances have identified triglyceride-rich lipoproteins [e.g., very LDL (VLDL)] as independent risk predictors for this disease. We have previously demonstrated peroxisome proliferator-activated receptor (PPAR)delta, but not PPARgamma, is the major nuclear VLDL sensor in the macrophage, which is a crucial component of the atherosclerotic lesion. Here, we show that, in addition to beta-oxidation and energy dissipation, activation of PPARdelta by VLDL particles induces key genes involved in carnitine biosynthesis and lipid mobilization mediated by a recently identified TG lipase, transport secretion protein 2 (also named desnutrin, iPLA2zeta, and adipose triglyceride lipase), resulting in increased fatty acid catabolism. Unexpectedly, deletion of PPARdelta results in derepression of target gene expression, a phenotype similar to that of ligand activation, suggesting that unliganded PPARdelta suppresses fatty acid utilization through active repression, which is reversed upon ligand binding. This unique transcriptional mechanism assures a tight control of the homeostasis of VLDL-derived fatty acid and provides a therapeutic target for other lipid-related disorders, including dyslipidemia and diabetes, in addition to coronary artery disease.

| S-EPMC1413732 | biostudies-literature

Low Sulfur Amino Acid, High Polyunsaturated Fatty Acid Diet Inhibits Breast Cancer Growth.

Project description:Cancer cells may acquire resistance to stress signals and reprogram metabolism to meet the energetic demands to support their high proliferation rate and avoid death. Hence, targeting nutrient dependencies of cancer cells has been suggested as a promising anti-cancer strategy. We explored the possibility of killing breast cancer (BC) cells by modifying nutrient availability. We used in vitro models of BC (MCF7 and MDA-MB-231) that were maintained with a low amount of sulfur amino acids (SAAs) and a high amount of oxidizable polyunsatured fatty acids (PUFAs). Treatment with anti-apoptotic, anti-ferroptotic and antioxidant drugs were used to determine the modality of cell death. We reproduced these conditions in vivo by feeding BC-bearing mice with a diet poor in proteins and SAAs and rich in PUFAs (LSAA/HPUFA). Western blot analysis, qPCR and histological analyses were used to assess the anti-cancer effects and the molecular pathways involved. We found that BC cells underwent oxidative damage to DNA and proteins and both apoptosis and ferroptosis were induced. Along with caspases-mediated PARP1 cleavage, we found a lowering of the GSH-GPX4 system and an increase of lipid peroxides. A LSAA/HPUFA diet reduced tumor mass and its vascularization and immune cell infiltration, and induced apoptosis and ferroptotic hallmarks. Furthermore, mitochondrial mass was found to be increased, and the buffering of mitochondrial reactive oxygen species limited GPX4 reduction and DNA damage. Our results suggest that administration of custom diets, targeting the dependency of cancer cells on certain nutrients, can represent a promising complementary option for anti-cancer therapy.

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Associations of polyunsaturated Fatty Acid intake with bone mineral density in postmenopausal women.

Project description:A secondary analysis of cross-sectional data was analyzed from 6 cohorts (Fall 1995-Fall 1997) of postmenopausal women (n = 266; 56.6 ± 4.7 years) participating in the Bone Estrogen Strength Training (BEST) study (a 12-month, block-randomized, clinical trial). Bone mineral density (BMD) was measured at femur neck and trochanter, lumbar spine (L2-L4), and total body BMD using dual-energy X-ray absorptiometry (DXA). Mean dietary polyunsaturated fatty acids (PUFAs) intakes were assessed using 8 days of diet records. Multiple linear regression was used to examine associations between dietary PUFAs and BMD. Covariates included in the models were total energy intake, body weight at year 1, years after menopause, exercise, use of hormone therapy (HT), total calcium, and total iron intakes. In the total sample, lumbar spine and total body BMD had significant negative associations with dietary PUFA intake at P < 0.05. In the non-HT group, no significant associations between dietary PUFA intake and BMD were seen. In the HT group, significant inverse associations with dietary PUFA intake were seen in the spine, total body, and Ward's triangle BMD, suggesting that HT may influence PUFA associations with BMD. This study is registered with clinicaltrials.gov, identifier: NCT00000399.

| S-EPMC4346685 | biostudies-literature

Altered hepatic catabolism of low-density lipoprotein subjected to lipid peroxidation in vitro.

Project description:Recent evidence suggests that oxidatively modified forms of low-density lipoprotein (LDL) may be particularly atherogenic. In this investigation, the catabolism of human LDL modified by lipid peroxidation in vitro was studied with a recirculating rat liver perfusion system. A dual-labelling technique was used that permitted native LDL and modified LDL to be studied simultaneously in the liver perfusion system. Native human LDL was found to have a fractional catabolic rate (FCR) of 1.00 +/- 0.21%/h, in agreement with other investigators. Subjecting LDL to oxidation for 12 h in the presence of 30 microM FeEDTA did not significantly affect its FCR. LDL treated with a superoxide-generating system (xanthine oxidase, hypoxanthine, O2) in the presence of 30 microM FeEDTA did, however, show a significant increase in FCR (3.23 +/- 0.19%/h). The hepatic uptakes of native LDL and LDL oxidized with FeEDTA+O2 were similar, but both were significantly lower than the hepatic uptake of LDL treated with the superoxide-radical-generating system. The proteolysis of LDL with pancreatin did not influence either its susceptibility to oxidation or its FCR. LDL oxidation resulted in the preferential loss of alpha-tocopherol rather than gamma-tocopherol. These data indicate that the rat liver effectively catabolizes LDL oxidatively modified by treatment with the superoxide-generating system. Furthermore, our results suggest that only very low plasma levels of highly oxidized LDL could be found under conditions in vivo. The liver may therefore play a major role in protecting the arterial vasculature from highly atherogenic forms of LDL.

| S-EPMC1137872 | biostudies-other

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