Nitro-fatty acid pharmacokinetics in the adipose tissue compartment

Journal of Lipid Research

NicholasK.H. Khoo¹  Lihua Li²  Diane K. Jorkasky³  Steven R. Woodcock³  Francisco J. Schopfer³  Bruce A. Freeman³  Marco Fazzari⁴ 

[1] Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261;Complexa Inc., Pittsburgh, PA 15203;Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261;Fondazione Ri.MED, 90133 Palermo, Italy;

关键词: adipocytes;    lipolysis and fatty acid metabolism;    metabolomics;    mass spectrometry;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown