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Nitro-fatty acids as activators of hSIRT6 deacetylase activity.

ABSTRACT: Sirtuin 6, SIRT6, is critical for both glucose and lipid homeostasis and is involved in maintaining genomic stability under conditions of oxidative DNA damage such as those observed in age-related diseases. There is an intense search for modulators of SIRT6 activity, however, not many specific activators have been reported. Long acyl-chain fatty acids have been shown to increase the weak in vitro deacetylase activity of SIRT6 but this effect is modest at best. Herein we report that electrophilic nitro-fatty acids (nitro-oleic acid and nitro-conjugated linoleic acid) potently activate SIRT6. Binding of the nitro-fatty acid to the hydrophobic crevice of the SIRT6 active site exerted a moderate activation (2-fold at 20 μm), similar to that previously reported for non-nitrated fatty acids. However, covalent Michael adduct formation with Cys-18, a residue present at the N terminus of SIRT6 but absent from other isoforms, induced a conformational change that resulted in a much stronger activation (40-fold at 20 μm). Molecular modeling of the resulting Michael adduct suggested stabilization of the co-substrate and acyl-binding loops as a possible additional mechanism of SIRT6 activation by the nitro-fatty acid. Importantly, treatment of cells with nitro-oleic acid promoted H3K9 deacetylation, whereas oleic acid had no effect. Altogether, our results show that nitrated fatty acids can be considered a valuable tool for specific SIRT6 activation, and that SIRT6 should be considered as a molecular target for in vivo actions of these anti-inflammatory nitro-lipids.

SUBMITTER: Carreno M

PROVIDER: S-EPMC7939442 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Nitro-fatty acids protect against steatosis and fibrosis during development of nonalcoholic fatty liver disease in mice

Project description:Lack of non-invasive diagnostic tools and effective therapies constitute two of the major hurdles for a bona fide treatment against non-alcoholic steatohepatitis (NASH) progression and/or regression of nonalcoholic fatty liver disease (NAFLD). Nitro-oleic acid (OA-NO2) has been proven effective in multiple experimental models of inflammation and fibrosis. Thus, the potential benefit of in vivo administration of OA-NO2 to treat advanced NAFLD was studied in a model of long-term NASH diet-induced liver damage. Non-invasive imaging (e.g. photoacustic-ultrasound (PA-US)) was pursued to establish advanced experimental NASH in mice in which both steatosis and fibrosis were diagnosed prior experimental OA-NO2 therapy. CLAMS and NMR-based analysis demonstrates that OA-NO2 improves body composition and energy metabolism and inhibits hepatic triglyceride accumulation. PA-US imaging revealed a robust inhibition of liver steatosis and fibrosis by OA-NO2. RNA-sequencing analysis uncovered inflammation and fibrosis as major pathways suppressed by OA-NO2 administration, as well as regulation of lipogenesis and lipolysis pathways, with a robust inhibition of SREBP1-dependent lipogenic gene expression by OA-NO2. Global liver transcriptome in response to OA-NO2 was confirmed in vivo and in isolated hepatocytes. These results were further supported by histological analysis and quantification of lipid accumulation, lobular inflammation (F4/80 staining) and fibrosis (collagen deposition, αSMA staining) as well as established parameters of liver damage (ALT). In vitro studies indicate that OA-NO2 inhibits TG biosynthesis and accumulation in hepatocytes and inhibits fibrogenesis in human stellate cells. Taken together, OA-NO2 improve steatohepatitis and fibrosis and may constitute an effective therapeutic approach against advanced NAFLD that warrants further clinical evaluation.

2019-02-08 | GSE126204 | GEO

Gas-phase fragmentation analysis of nitro-fatty acids.

Project description:Nitro-fatty acids are electrophilic signaling mediators formed in increased amounts during inflammation by nitric oxide and nitrite-dependent redox reactions. A more rigorous characterization of endogenously-generated species requires additional understanding of their gas-phase induced fragmentation. Thus, collision induced dissociation (CID) of nitroalkane and nitroalkene groups in fatty acids were studied in the negative ion mode to provide mass spectrometric tools for their structural characterization. Fragmentation of nitroalkanes occurred mainly through loss of the NO(2)(-) anion or neutral loss of HNO(2). The CID of nitroalkenes proceeds via a more complex cyclization, followed by fragmentation to nitrile and aldehyde products. Gas-phase fragmentation of nitroalkene functional groups with additional ? or ? unsaturation occurred through a multiple step cyclization reaction process, leading to 5 and 6 member ring heterocyclic products and carbon chain fragmentation. Cyclization products were not obtained during nitroalkane fragmentation, highlighting the role of double bond ? electrons during NO(2)(-) rearrangements, stabilization and heterocycle formation. The proposed structures, mechanisms and products of fragmentation are supported by analysis of (13)C and (15)N labeled parent molecules, 6 different nitroalkene positional isomers, 6 nitroalkane positional isomers, accurate mass determinations at high resolution and quantum mechanics calculations. Multiple key diagnostic ion fragments were obtained through this analysis, allowing for the precise placement of double bonds and sites of fatty acid nitration, thus supporting an ability to predict nitro positions in biological samples.

| S-EPMC3286133 | biostudies-literature

Topical electrophilic nitro-fatty acids potentiate cutaneous inflammation.

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| S-EPMC5767521 | biostudies-literature

Inflammatory signaling and metabolic regulation by nitro-fatty acids.

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| S-EPMC6151155 | biostudies-literature

Chemoproteomic profiling reveals cellular targets of nitro-fatty acids.

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| S-EPMC8441202 | biostudies-literature

Electrophilic nitro-fatty acids suppress allergic contact dermatitis in mice.

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| S-EPMC5352476 | biostudies-literature

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2024-03-26 | PXD023372 | Pride

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| S-EPMC7278747 | biostudies-literature

Nitro-fatty acids suppress ischemic ventricular arrhythmias by preserving calcium homeostasis.

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| S-EPMC7501300 | biostudies-literature

Short-chain fatty acids enhance nuclear receptor activity through mitogen-activated protein kinase activation and histone deacetylase inhibition.

Project description:In this study, we demonstrate that the pervasive xenobiotic methoxyacetic acid and the commonly prescribed anticonvulsant valproic acid, both short-chain fatty acids (SCFAs), dramatically increase cellular sensitivity to estrogens, progestins, and other nuclear hormone receptor ligands. These compounds do not mimic endogenous hormones but rather act to enhance the transcriptional efficacy of ligand activated nuclear hormone receptors by up to 8-fold in vitro and in vivo. Detailed characterization of their mode of action revealed that these SCFAs function as both activators of p42/p44 mitogen-activated protein kinase and as inhibitors of histone deacetylases at doses that parallel known exposure levels. Our results define a class of compounds that possess a dual mechanism of action and function as hormone sensitizers. These findings prompt an evaluation of previously unrecognized drug-drug interactions in women who are administered exogenous hormones while exposed to certain xenobiotic SCFAs. Furthermore, our study highlights the need to structure future screening programs to identify additional hormone sensitizers.

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