Nitro-fatty acid formation and signaling.
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ABSTRACT:
SUBMITTER: Freeman BA
PROVIDER: S-EPMC2414282 | biostudies-literature | 2008 Jun
REPOSITORIES: biostudies-literature
Publications
Nitro-fatty acid formation and signaling.
Freeman Bruce A BA Baker Paul R S PR Schopfer Francisco J FJ Woodcock Steven R SR Napolitano Alessandra A d'Ischia Marco M
The Journal of biological chemistry 20080219 23
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Project description:RATIONALE:Fatty acid nitroalkenes are endogenously generated electrophilic byproducts of nitric oxide and nitrite-dependent oxidative inflammatory reactions. Existing evidence indicates nitroalkenes support posttranslational protein modifications and transcriptional activation that promote the resolution of inflammation. OBJECTIVE:The aim of this study was to assess whether in vivo administration of a synthetic nitroalkene could elicit antiinflammatory actions in vivo using a murine model of vascular injury. METHODS AND RESULTS:The in vivo administration (21 days) of nitro-oleic acid (OA-NO(2)) inhibited neointimal hyperplasia after wire injury of the femoral artery in a murine model (OA-NO(2) treatment resulted in reduced intimal area and intima to media ratio versus vehicle- or oleic acid (OA)-treated animals,P<0.0001). Increased heme oxygenase (HO)-1 expression accounted for much of the vascular protection induced by OA-NO(2) in both cultured aortic smooth muscle cells and in vivo. Inhibition of HO by Sn(IV)-protoporphyrin or HO-1 small interfering RNA reversed OA-NO(2)-induced inhibition of platelet-derived growth factor-stimulated rat aortic smooth muscle cell migration. The upregulation of HO-1 expression also accounted for the antistenotic actions of OA-NO(2) in vivo, because inhibition of neointimal hyperplasia following femoral artery injury was abolished in HO-1(-/-) mice (OA-NO(2)-treated wild-type versus HO-1(-/-) mice, P=0.016). CONCLUSIONS:In summary, electrophilic nitro-fatty acids induce salutary gene expression and cell functional responses that are manifested by a clinically significant outcome, inhibition of neointimal hyperplasia induced by arterial injury.
| S-EPMC2784279 | biostudies-literature
Project description:Inflammation, characterized by the activation of both resident and infiltrated immune cells, is accompanied by increased production of oxidizing and nitrating species. Nitrogen dioxide, the proximal nitrating species formed under these conditions, reacts with unsaturated fatty acids to yield nitroalkene derivatives. These electrophilic products modulate protein function via post-translational modification of susceptible nucleophilic amino acids. Nitroalkenes react with Keap1 to instigate Nrf2 signaling, activate heat shock response gene expression, and inhibit NF-κB-mediated signaling, inducing net anti-inflammatory and tissue-protective metabolic responses. We report the purification and characterization of a NADPH-dependent liver enzyme that reduces the nitroalkene moiety of nitro-oleic acid, yielding the inactive product nitro-stearic acid. Prostaglandin reductase-1 (PtGR-1) was identified as a nitroalkene reductase by protein purification and proteomic studies. Kinetic measurements, inhibition studies, immunological and molecular biology approaches as well as clinical analyses confirmed this identification. Overexpression of PtGR-1 in HEK293T cells promoted nitroalkene metabolism to inactive nitroalkanes, an effect that abrogated the Nrf2-dependent induction of heme oxygenase-1 expression by nitro-oleic acid. These results situate PtGR-1 as a critical modulator of both the steady state levels and signaling activities of fatty acid nitroalkenes in vivo.
| S-EPMC3757223 | biostudies-literature
Project description:Nitrated derivatives of unsaturated fatty acids are endogenously formed under oxidative and nitrative stress condition and are defined as electrophilic fatty acids containing a nitro group to a carbon-carbon double bond. Among the most studied nitro derivatives of unsaturated fatty acids are nitro-oleic acid (OA-NO2) and nitro-linoleic acid (LNO2). These products exhibit novel protective actions in a variety of rodent disease models. Diverse signaling events are responsible for effects of nitrated fatty acid, including activating peroxisome proliferator-activated receptor-dependent gene expression, suppressing NF-κB-induced inflammation, inhibiting oxidative stress, and increasing both endothelial nitric oxide synthase- and Nrf2-dependent gene regulation. Nitrated fatty acids have been emerging not only as a unique class of signaling molecules produced endogenously and but also as multipotent modulators of cell signaling pathways in cardiovascular and renal diseases. In this review, we discuss biochemical properties of nitrated fatty acid and its signaling pathways in the modulation of cellular events. A major focus is to review recent knowledge of nitrated fatty acid on the treatment of kidney diseases and its therapeutic potential for inflammation and metabolic disorders, with special emphasis on acute kidney injury and diabetic kidney disease.
| S-EPMC4835926 | biostudies-literature
Project description:Electrophilic nitro-FAs (NO2-FAs) promote adaptive and anti-inflammatory cell signaling responses as a result of an electrophilic character that supports posttranslational protein modifications. A unique pharmacokinetic profile is expected for NO2-FAs because of an ability to undergo reversible reactions including Michael addition with cysteine-containing proteins and esterification into complex lipids. Herein, we report via quantitative whole-body autoradiography analysis of rats gavaged with radiolabeled 10-nitro-[14C]oleic acid, preferential accumulation in adipose tissue over 2 weeks. To better define the metabolism and incorporation of NO2-FAs and their metabolites in adipose tissue lipids, adipocyte cultures were supplemented with 10-nitro-oleic acid (10-NO2-OA), nitro-stearic acid, nitro-conjugated linoleic acid, and nitro-linolenic acid. Then, quantitative HPLC-MS/MS analysis was performed on adipocyte neutral and polar lipid fractions, both before and after acid hydrolysis of esterified FAs. NO2-FAs preferentially incorporated in monoacyl- and diacylglycerides, while reduced metabolites were highly enriched in triacylglycerides. This differential distribution profile was confirmed in vivo in the adipose tissue of NO2-OA-treated mice. This pattern of NO2-FA deposition lends new insight into the unique pharmacokinetics and pharmacologic actions that could be expected for this chemically-reactive class of endogenous signaling mediators and synthetic drug candidates.
| S-EPMC5282953 | biostudies-literature
Project description:The addition of nitrogen dioxide (NO2) to the double bond of unsaturated fatty acids yields an array of electrophilic nitro-fatty acids (NO2-FA) with unique biochemical and signaling properties. During the last decade, NO2-FA have been shown to exert a protective role in various inflammatory and metabolic disorders. NO2-FA exert their biological effects primarily by regulating two central physiological adaptive responses: the canonical inflammatory signaling and metabolic pathways. In this mini-review, we summarize current knowledge on the regulatory role of NO2-FA in the inflammatory and metabolic response via regulation of nuclear factor kappa B (NF-?B) and peroxisome proliferator-activated receptor ? (PPAR?), master regulators of inflammation and metabolism. Moreover, the engagement of novel signaling and metabolic pathways influenced by NO2-FA, beyond NF-?B and PPAR signaling, is discussed herein.
| S-EPMC6151155 | biostudies-literature
Project description:Main conclusionNitro fatty acids (NO2-FA)have relevant physiological roles as signaling molecules in biotic and abiotic stress, growth, and development, but the mechanism of action remains controversial. The two main mechanisms involving nitric oxide release and thiol modification are discussed. Fatty acids (FAs) are major components of membranes and contribute to cellular energetic demands. Besides, FAs are precursors of signaling molecules, including oxylipins and other oxidized fatty acids derived from the activity of lipoxygenases. In addition, non-canonical modified fatty acids, such as nitro-fatty acids (NO2-FAs), are formed in animals and plants. The synthesis NO2-FAs involves a nitration reaction between unsaturated fatty acids and reactive nitrogen species (RNS). This review will focus on recent findings showing that, in plants, NO2-FAs such as nitro-linolenic acid (NO2-Ln) and nitro-oleic acid (NO2-OA) have relevant physiological roles as signaling molecules in biotic and abiotic stress, growth, and development. Moreover, since there is controversy on mechanisms of action of NO2-FAs as signaling molecules, we will provide evidence showing why this aspect needs further evaluation.
| S-EPMC10704571 | biostudies-literature
Project description:Fatty acids (FAs) are typically associated with structural and metabolic roles, as they can be stored as triglycerides, degraded by β-oxidation or used in phospholipids' synthesis, the main components of biological membranes. It has been shown that these lipids exhibit also regulatory functions in different cell types. FAs can serve as secondary messengers, as well as modulators of enzymatic activities and substrates for cytokines synthesis. More recently, it has been documented a direct activity of free FAs as ligands of membrane, cytosolic, and nuclear receptors, and cumulative evidence has emerged, demonstrating its participation in a wide range of physiological and pathological conditions. It has been long known that the central nervous system is enriched with poly-unsaturated FAs, such as arachidonic (C20:4ω-6) or docosohexaenoic (C22:6ω-3) acids. These lipids participate in the regulation of membrane fluidity, axonal growth, development, memory, and inflammatory response. Furthermore, a whole family of low molecular weight compounds derived from FAs has also gained special attention as the natural ligands for cannabinoid receptors or key cytokines involved in inflammation, largely expanding the role of FAs as precursors of signaling molecules. Nutritional deficiencies, and alterations in lipid metabolism and lipid signaling have been associated with developmental and cognitive problems, as well as with neurodegenerative diseases. The molecular mechanism behind these effects still remains elusive. But in the last two decades, different families of proteins have been characterized as receptors mediating FAs signaling. This review focuses on different receptors sensing and transducing free FAs signals in neural cells: (1) membrane receptors of the family of G Protein Coupled Receptors known as Free Fatty Acid Receptors (FFARs); (2) cytosolic transport Fatty Acid-Binding Proteins (FABPs); and (3) transcription factors Peroxisome Proliferator-Activated Receptors (PPARs). We discuss how these proteins modulate and mediate direct regulatory functions of free FAs in neural cells. Finally, we briefly discuss the advantages of evaluating them as potential targets for drug design in order to manipulate lipid signaling. A thorough characterization of lipid receptors of the nervous system could provide a framework for a better understanding of their roles in neurophysiology and, potentially, help for the development of novel drugs against aging and neurodegenerative processes.
| S-EPMC6491900 | biostudies-literature
Project description:Endothelial cell (EC) CD36 controls tissue fatty acid (FA) uptake. Here we examine how ECs transfer FAs. FA interaction with apical membrane CD36 induces Src phosphorylation of caveolin-1 tyrosine-14 (Cav-1Y14) and ceramide generation in caveolae. Ensuing fission of caveolae yields vesicles containing FAs, CD36 and ceramide that are secreted basolaterally as small (80-100 nm) exosome-like extracellular vesicles (sEVs). We visualize in transwells EC transfer of FAs in sEVs to underlying myotubes. In mice with EC-expression of the exosome marker emeraldGFP-CD63, muscle fibers accumulate circulating FAs in emGFP-labeled puncta. The FA-sEV pathway is mapped through its suppression by CD36 depletion, blocking actin-remodeling, Src inhibition, Cav-1Y14 mutation, and neutral sphingomyelinase 2 inhibition. Suppression of sEV formation in mice reduces muscle FA uptake, raises circulating FAs, which remain in blood vessels, and lowers glucose, mimicking prominent Cd36-/- mice phenotypes. The findings show that FA uptake influences membrane ceramide, endocytosis, and EC communication with parenchymal cells.
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Project description:Retinoic acid (RA) is a metabolite of vitamin A and is essential for development and growth as well as cellular metabolism. Through genomic and nongenomic actions, RA regulates a variety of physiological functions. Dysregulation of RA signaling is associated with many diseases. Targeting RA signaling has been proven valuable to human health. All-trans retinoic acid (AtRA) and anthracycline-based chemotherapy are the standard treatment of acute promyelocytic leukemia (APL). Both human and animal studies have shown a significant relationship between RA signaling and the development and progression of nonalcoholic fatty liver disease (NAFLD). In this review article, we will first summarize vitamin A metabolism and then focus on the role of RA signaling in NAFLD. AtRA inhibits the development and progression of NAFLD via regulating lipid metabolism, inflammation, thermogenesis, etc.
| S-EPMC10583737 | biostudies-literature
Project description:Endothelial cell (EC) CD36 controls tissue fatty acid (FA) uptake. Here we examined how ECs transfer FAs. FA interaction with apical membrane CD36 induced Src phosphorylation of caveolin-1 tyrosine-14 (Cav-1Y14) and ceramide generation in caveolae. Fission of the caveolae yielded vesicles containing FAs, CD36 and ceramide that were secreted basolaterally as small (80-100nm) exosome-like extracellular vesicles (sEVs). We visualized EC transfer of FAs in sEVs to underlying myotubes in transwells. In mice with EC-expression of the exosome marker emeraldGFP-CD63, muscle fibers accumulated circulating FAs in emGFP-labeled puncta. The FA-sEV pathway was mapped through its suppression by CD36 depletion, blocking actin-remodeling, Src inhibition, Cav-1Y14 mutation, and neutral sphingomyelinase 2 inhibition. Suppression of sEV formation in mice reduced muscle FA uptake, raised circulating FAs, which remained in blood vessels, and lowered glucose, mimicking prominent Cd36-/- phenotypes. The findings show that FA uptake influences membrane ceramide, endocytosis, and EC communication with parenchymal cells.
2023-07-02 | GSE235988 | GEO