title: Nitro-fatty acid pharmacokinetics in the adipose tissue compartment.
abstract: 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.
authors.affiliation: Fondazione Ri.MED, 90133 Palermo, Italy.|Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261.
authors.forename: Marco
authors.initials: M
authors.lastname: Fazzari
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261.
authors.forename: Nicholas K H
authors.initials: NK
authors.lastname: Khoo
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Woodcock
authors.affiliation: Complexa Inc., Pittsburgh, PA 15203.
authors.forename: Diane K
authors.initials: DK
authors.lastname: Jorkasky
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261.
authors.forename: Lihua
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261 freerad@pitt.edu fjs2@pitt.edu.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Schopfer
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261 freerad@pitt.edu fjs2@pitt.edu.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Freeman
mesh_terms: D000273:Adipose Tissue / Q000737:chemistry / Q000378:metabolism*; D000475:Alkenes / Q000737:chemistry; D000818:Animals; D002250:Carbon Radioisotopes / Q000737:chemistry; D003545:Cysteine / Q000737:chemistry; D004951:Esterification; D005227:Fatty Acids / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D009569:Nitric Oxide / Q000737:chemistry / Q000378:metabolism; D009829:Oleic Acids / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D053719:Tandem Mass Spectrometry
chemical_list: C521487:10-nitro-oleic acid; D000475:Alkenes; D002250:Carbon Radioisotopes; D005227:Fatty Acids; D009829:Oleic Acids; D009569:Nitric Oxide; D003545:Cysteine
keywords: adipocytes; lipolysis and fatty acid metabolism; mass spectrometry; metabolomics