Inflammatory signaling and metabolic regulation by nitro-fatty acids

Rom, Oren; Khoo, Nicholas K.H.; Chen, Y. Eugene; Villacorta, Luis

doi:10.1016/j.niox.2018.03.017

Cited by 17 publications

(19 citation statements)

References 72 publications

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“…These electrophilic species have a partial positive charge on the  carbon of the vinyl nitro substituent, which supports reversible Michael addition reactions with nucleophilic thiols of GSH and cysteine-containing proteins (16). By altering the structure and function of multiple thiolcontaining transcriptional regulatory proteins, such as NF-kB p65 subunit, Keap1, stimulator of interferon genes (STING), and PPAR-, NO 2 -FAs modulate the expression of more than 300 genes crucial for cytoprotective, metabolic, and anti-inflammatory responses (38)(39)(40). In addition to the electrophilic character of 10-NO 2 -OA, its PK is also influenced by: a) esterification into PLs and TAGs (25,41); b) inactivation upon PtGR-1 reduction to the nonelectrophilic nitroalkane, 10-NO 2 -SA (33); c) and -oxidation reactions to yield shorter chain length dicarboxylate products (27,42); and d) isomerization to the corresponding geometric (Z)-isomer (43).…”

Section: Biodistribution and Metabolism Of 10-no 2 -Oa In Plasma Lipidsmentioning

confidence: 77%

“…The sn-1/sn-3 and sn-2 fatty acid position on the glycerol backbone of this species was determined by comparing the ion intensity of the MS 2 fragments. This showed mono-and polyunsaturated fatty acids predominantly in sn-1/sn-3 position and 10-NO 2 -OA in the sn-2 position (35)(36)(37)(38). On the basis of the relative peak area, 18:1/10-NO 2 -OA/18:2-TAG was the most abundant species with an odd mass of m/z 945.77.…”

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confidence: 94%

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Electrophilic fatty acid nitroalkenes are systemically transported and distributed upon esterification to complex lipids

Fazzari

Vitturi

Woodcock

et al. 2019

Journal of Lipid Research

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The knowledge of absorption, distribution, metabolism, and excretion (ADME) of new drug candidates is important for safe and insightful development. The rate of drug development failures attributable to ADME deficiencies exceeds 40% and, even after new drug approval, many drugs still display ADME problems. Notably, "a chemical cannot be a drug, no matter how active nor how specific its action, unless it is also taken appropriately into the body (absorption), distributed to the right parts of the body, metabolized in a way that does not instantly remove its activity, and eliminated in a suitable manner" (Ref. 1; p. 722). As a covalently acting endogenous mediator and a class of new drug candidates, electrophilic nitro-fatty acids [NO 2 -FAs (fatty acid nitroalkenes)] have displayed beneficial effects in preclinical animal models of metabolic and inflammatory disease (2-7). A synthetic homolog of a NO 2 -FA detected in plants and mammals (8,9), (E)-10-nitro-octadec-9-enoic acid [10-nitro-oleic acid (10-NO 2 -OA)], is now in phase 2 clinical trials for treating focal segmental glomerulosclerosis and will soon begin trials in pulmonary arterial hypertension and obese asthmatics.NO 2 -FAs are generated during inflammation and digestion by reactions between unsaturated fatty acids and the Abstract Electrophilic nitro-fatty acids [NO 2 -FAs (fatty acid nitroalkenes)] showed beneficial signaling actions in preclinical studies and safety in phase 1 clinical trials. A detailed description of the pharmacokinetics (PK) of NO 2 -FAs is complicated by the capability of electrophilic fatty acids to alkylate thiols reversibly and become esterified in various complex lipids, and the instability of the nitroalkene moiety during enzymatic and base hydrolysis. Herein, we report the mechanism and kinetics of absorption, metabolism, and distribution of the endogenously detectable and prototypical NO 2 -FA, 10-nitro-oleic acid (10-NO 2 -OA), in dogs after oral administration. Supported by HPLC-high-resolution-MS/MS analysis of synthetic and plasma-derived 10-NO 2 -OA-containing triacylglycerides (TAGs), we show that a key mechanism of NO 2 -FA distribution is an initial esterification into complex lipids. Quantitative analysis of plasma free and esterified lipid fractions confirmed time-dependent preferential incorporation of 10-NO 2 -OA into TAGs when compared with its principal metabolite, 10-nitro-stearic acid. Finally, new isomers of 10-NO 2 -OA were identified in vivo, and their electrophilic reactivity and metabolism characterized. Overall, we reveal that NO 2 -FAs display unique PK, with the principal mechanism of tissue distribution involving complex lipid esterification, which serves to shield the electrophilic character of this mediator from plasma and hepatic inactivation and thus permits efficient distribution to target organs.-Fazzari, M., D. A. Vitturi, S. R. Woodcock, S. R. Salvatore, B. A. Freeman, and F. J. Schopfer. Electrophilic fatty acid nitroalkenes are systemically transported and distributed upon esterification ...

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Section: Biodistribution and Metabolism Of 10-no 2 -Oa In Plasma Lipidsmentioning

confidence: 77%

mentioning

confidence: 94%

Electrophilic fatty acid nitroalkenes are systemically transported and distributed upon esterification to complex lipids

Fazzari

Vitturi

Woodcock

et al. 2019

Journal of Lipid Research

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“…Nitroalkene derivatives of unsaturated fatty acids (NO 2 -FAs) have emerged as potent anti-inflammatory and anti-fibrotic signaling mediators [8,9]. NO 2 -FAs are generated during inflammation and digestion through non-enzymatic reactions of unsaturated fatty acids with nitrogen dioxide ( .…”

Section: Introductionmentioning

confidence: 99%

“…NO 2 ), yielding an array of electrophilic NO 2 -FAs with unique biochemical and signaling properties [10,11]. Nitro-oleic acid (OA-NO 2 ), exerts protective roles in numerous experimental models of inflammation, imbalanced lipid metabolism and fibrosis [9]. These include endotoxin-induced vascular inflammation and multi-organ injury [12,13], colitis [14], atherosclerosis [15], systemic and pulmonary arterial hypertension (PAH) [16,17], atrial fibrillation and myocardial fibrosis [18,19].…”

Section: Introductionmentioning

confidence: 99%

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

Rom

Guo

et al. 2019

EBioMedicine

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Background Nonalcoholic fatty liver disease (NAFLD) and resulting nonalcoholic steatohepatitis (NASH) are reaching global epidemic proportions. Lack of non-invasive diagnostic tools and effective therapies constitute two of the major hurdles for a bona fide treatment and a reversal of NASH progression and/or regression of the disease. Nitro-oleic acid (OA-NO 2 ) has been proven effective in multiple experimental models of inflammation and fibrosis. Thus, the potential benefit of in vivo administration of OA-NO 2 to treat advanced NAFLD was tested herein in a model of long-term NASH diet-induced liver damage. Methods Non-invasive imaging (e.g. photoacustic-ultrasound (PA-US)) was pursued to establish advanced experimental model of NASH in mice in which both steatosis and fibrosis were diagnosed prior experimental therapy with OA-NO 2 . Experimental controls included equimolar amounts of the non-nitrated oleic acid (OA). CLAMS and NMR-based analysis was used for energy metabolism. Findings CLAMS and NMR-based analysis demonstrates that OA-NO 2 improves body composition and energy metabolism and inhibits hepatic triglyceride (TG) accumulation. Photoacoustic-ultrasound imaging revealed a robust inhibition of liver steatosis and fibrosis by OA-NO 2 . RNA-sequencing analysis uncovered inflammation and fibrosis as major pathways suppressed by OA-NO 2 administration, as well as regulation of lipogenesis and lipolysis pathways, with a robust inhibition of SREBP1 proteolytic activation and subsequent lipogenesis gene expression by OA-NO 2 . 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-NO 2 inhibits TG biosynthesis and accumulation in hepatocytes and inhibits fibrogenesis in human stellate cells. Interpretation OA-NO 2 improve steatohepatitis and fibrosis and may constitute an effective therapeutic approach against advanced NAFLD that warrants further clinical evaluation.

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“…10‐nitro‐9(E)‐octadec‐9‐enoic acid (CXA‐10) is a specific regioisomer of OA‐NO 2 , characterized by a nitro group on carbon 10 with effects similar to the mixed isomer. NFAs, in general, and CXA‐10, in particular, demonstrate potential as effective therapeutic agents in multiple disease indications in which metabolic and oxidative stress, inflammation, fibrosis, and/or direct tissue toxicity play significant roles …”

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confidence: 99%

Pharmacokinetic and Pharmacodynamic Effects of OralCXA‐10, a Nitro Fatty Acid, After Single and Multiple Ascending Doses in Healthy and Obese Subjects

Garner¹,

Mould

Chieffo³

et al. 2019

Clinical Translational Sci

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10‐nitro‐9(E)‐octadec‐9‐enoic acid (CXA‐10), a novel nitro fatty acid compound, demonstrates potential as a therapeutic agent in multiple disease indications in which oxidative stress, inflammation, fibrosis, and/or direct tissue toxicity play significant roles. Phase I studies were conducted in healthy and obese subjects to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of oral CXA‐10 after single and multiple doses in the fed and fasted states that would confirm the mechanisms of action of CXA‐10. After single and multiple ascending doses, CXA‐10 demonstrated dose‐proportional increases in plasma exposure. CXA‐10 decreased levels of biomarkers associated with altered inflammation and metabolic stress observed from nonclinical studies. In CXA‐10‐202, a consistent decrease from baseline was observed with CXA‐10 150 mg dose, but not 25 or 450 mg doses, for biomarkers of altered inflammation and metabolic dysfunction, including leptin, triglycerides, cholesterol, MCP‐1, and IL‐6. In CXA‐10‐203, after coadministration with CXA‐10, geometric mean peak plasma concentration (Cmax) and area under the plasma concentration‐time curve from time point 0 to the end of the dosing interval (AUC0−t) decreased 20% and 25% for pravastatin, increased 10% and 25% for simvastatin, and decreased 20% and 5% for ezetimibe. These findings are consistent with the pharmacological effects of CXA‐10. Adverse events (AEs) were dose‐related, and the most frequently reported AEs (>10% of subjects) were diarrhea, abdominal pain, and nausea. CXA‐10 was safe and well‐tolerated with no clinically significant abnormalities reported on physical examination, vital signs, clinical laboratory evaluations, or electrocardiographic evaluation. Phase II studies are underway in patients with focal segmental glomerulosclerosis and pulmonary arterial hypertension to investigate the efficacy and tolerability of CXA‐10 75–300 mg once daily.

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Inflammatory signaling and metabolic regulation by nitro-fatty acids

Cited by 17 publications

References 72 publications

Electrophilic fatty acid nitroalkenes are systemically transported and distributed upon esterification to complex lipids

Electrophilic fatty acid nitroalkenes are systemically transported and distributed upon esterification to complex lipids

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

Pharmacokinetic and Pharmacodynamic Effects of OralCXA‐10, a Nitro Fatty Acid, After Single and Multiple Ascending Doses in Healthy and Obese Subjects

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