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FASEB J. 2019 Jun;33(6):7072-7083. doi: 10.1096/fj.201802587R. Epub 2019 Mar 6.

Leukocytes from obese individuals exhibit an impaired SPM signature.

Author information

1
Biochemistry and Molecular Genetics Service, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.
2
Department of Biomedical Sciences, University of Barcelona, Barcelona, Spain.
3
Lipid Mediator Unit, Biochemical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, United Kingdom.
4
Centre for Inflammation and Therapeutic Innovation, Queen Mary University of London, London, United Kingdom.
5
Surgery Department, Hospital Universitari Mútua Terrassa, Terrassa, Spain.
6
Gastroenterology Department, Hospital Universitari Mútua Terrassa, Terrassa, Spain.
7
European Foundation for the Study of Chronic Liver Failure (EF Clif), Barcelona, Spain.

Abstract

Specialized proresolving mediators (SPMs) biosynthesized from docosahexaenoic acids (DHAs) including resolvins (Rvs), protectins, and maresins are potent endogenous autacoids that actively resolve inflammation, protect organs, and stimulate tissue regeneration. Our hypothesis was that failure of resolution programs may lead to unremitting inflammation in obesity, contributing to the development of metabolic comorbidities in this condition. Obese individuals with persistent low-grade systemic inflammation showed reduced leukocyte production of the DHA-derived monohydroxy fatty acid 17-hydroxy-DHA (HDHA) and unbalanced formation of SPMs (in particular D-series Rvs) accompanied by enhanced production of proinflammatory lipid mediators such as leukotriene B4. Mechanistic studies attributed this impairment to reduced 15-lipoxygenase (LOX) activity rather than altered DHA cellular uptake. Moreover, leukocytes from obese individuals exhibited decreased 5-LOX levels and reduced 5-LOX Ser271 phosphorylation and distinct intracellular 5-LOX redistribution. However, 15-LOX appears to be the most critical factor for the deficient production of SPMs by obese leukocytes because the formation of D-series Rvs was completely rescued by incubation with the intermediate precursor 17-HDHA. These data provide proof of concept that administration of intermediate precursors of SPM biosynthesis (e.g., 17-HDHA) could be more efficient in overriding impaired formation of these proresolving lipid mediators in conditions characterized by dysfunctional LOX activity, such as obesity.-López-Vicario, C., Titos, E., Walker, M. E., Alcaraz-Quiles, J., Casulleras, M., Durán-Güell, M., Flores-Costa, R., Pérez-Romero, N., Forné, M., Dalli, J., Clària, J. Leukocytes from obese individuals exhibit an impaired SPM signature.

KEYWORDS:

lipoxygenases; obesity; specialized proresolving mediator

PMID:
30840838
DOI:
10.1096/fj.201802587R
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