The Soluble Epoxide Hydrolase Inhibitor GSK2256294 Decreases the Proportion of Adipose Pro-inflammatory T Cells

Overview

Journal Prostaglandins Other Lipid Mediat

Date 2021 Dec 18

PMID 34922004

Citations 2

Authors

Mona Mashayekhi

Celestine N Wanjalla

Christian M Warren

Joshua D Simmons

Kakali Ghoshal

Mark Pilkinton

Samuel S Bailin

Curtis L Gabriel

Ambra Pozzi

John R Koethe

Nancy J Brown

Spyros A Kalams

J Matthew Luther

Affiliations

Soon will be listed here.

Abstract

Adipose tissue contains a complex immune environment and is a central contributor to heightened systemic inflammation in obese persons. Epoxyeicosatrienoic acids (EETs) are lipid signaling molecules that decrease inflammation in obese animals, but their effect on inflammation in humans is unknown. The enzyme soluble epoxide hydrolase (sEH) hydrolyzes EETs to less active diols, and we hypothesized that pharmacologic sEH inhibition would decrease adipose inflammation in obese individuals. We treated obese prediabetic adults with the sEH inhibitor GSK2256294 versus placebo in a crossover design, collected subcutaneous abdominal adipose tissue via lipoaspiration and characterized the tissue T cell profile. Treatment with GSK2256294 decreased the percentage of pro-inflammatory T cells producing interferon-gamma (IFNγ), but not interleukin (IL)-17A, and decreased the amount of secreted tumor necrosis factor-alpha (TNFα). Understanding the contribution of the EET/sEH pathway to inflammation in obesity could lead to new strategies to modulate adipose and systemic inflammation.

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References

Saltiel A, Olefsky J . Inflammatory mechanisms linking obesity and metabolic disease. J Clin Invest. 2017; 127(1):1-4. PMC: 5199709. DOI: 10.1172/JCI92035. View

Russo L, Lumeng C . Properties and functions of adipose tissue macrophages in obesity. Immunology. 2018; 155(4):407-417. PMC: 6230999. DOI: 10.1111/imm.13002. View

Neeland I, Poirier P, Despres J . Cardiovascular and Metabolic Heterogeneity of Obesity: Clinical Challenges and Implications for Management. Circulation. 2018; 137(13):1391-1406. PMC: 5875734. DOI: 10.1161/CIRCULATIONAHA.117.029617. View

Golia E, Limongelli G, Natale F, Fimiani F, Maddaloni V, Pariggiano I . Inflammation and cardiovascular disease: from pathogenesis to therapeutic target. Curr Atheroscler Rep. 2014; 16(9):435. DOI: 10.1007/s11883-014-0435-z. View

Luther J, Brown N . Epoxyeicosatrienoic acids and glucose homeostasis in mice and men. Prostaglandins Other Lipid Mediat. 2016; 125:2-7. PMC: 5035218. DOI: 10.1016/j.prostaglandins.2016.07.010. View

Gangadhariah M, Dieckmann B, Lantier L, Kang L, Wasserman D, Chiusa M . Cytochrome P450 epoxygenase-derived epoxyeicosatrienoic acids contribute to insulin sensitivity in mice and in humans. Diabetologia. 2017; 60(6):1066-1075. PMC: 5921930. DOI: 10.1007/s00125-017-4260-0. View

Dai M, Wu L, Wang P, Wen Z, Xu X, Wang D . CYP2J2 and Its Metabolites EETs Attenuate Insulin Resistance via Regulating Macrophage Polarization in Adipose Tissue. Sci Rep. 2017; 7:46743. PMC: 5404269. DOI: 10.1038/srep46743. View

Vegiopoulos A, Rohm M, Herzig S . Adipose tissue: between the extremes. EMBO J. 2017; 36(14):1999-2017. PMC: 5509999. DOI: 10.15252/embj.201696206. View

Theken K, Lee C . Genetic variation in the cytochrome P450 epoxygenase pathway and cardiovascular disease risk. Pharmacogenomics. 2007; 8(10):1369-83. DOI: 10.2217/14622416.8.10.1369. View

10.

Abraham N, Sodhi K, Silvis A, Vanella L, Favero G, Rezzani R . CYP2J2 targeting to endothelial cells attenuates adiposity and vascular dysfunction in mice fed a high-fat diet by reprogramming adipocyte phenotype. Hypertension. 2014; 64(6):1352-61. PMC: 4230994. DOI: 10.1161/HYPERTENSIONAHA.114.03884. View

11.

Liu L, Puri N, Raffaele M, Schragenheim J, Singh S, Bradbury J . Ablation of soluble epoxide hydrolase reprogram white fat to beige-like fat through an increase in mitochondrial integrity, HO-1-adiponectin in vitro and in vivo. Prostaglandins Other Lipid Mediat. 2018; 138:1-8. PMC: 6314013. DOI: 10.1016/j.prostaglandins.2018.07.004. View

12.

Kohlgruber A, Lynch L . Adipose tissue inflammation in the pathogenesis of type 2 diabetes. Curr Diab Rep. 2015; 15(11):92. DOI: 10.1007/s11892-015-0670-x. View

13.

Waldman M, Bellner L, Vanella L, Schragenheim J, Sodhi K, Singh S . Epoxyeicosatrienoic Acids Regulate Adipocyte Differentiation of Mouse 3T3 Cells, Via PGC-1α Activation, Which Is Required for HO-1 Expression and Increased Mitochondrial Function. Stem Cells Dev. 2016; 25(14):1084-94. PMC: 4939374. DOI: 10.1089/scd.2016.0072. View

14.

Schmelzer K, Kubala L, Newman J, Kim I, Eiserich J, Hammock B . Soluble epoxide hydrolase is a therapeutic target for acute inflammation. Proc Natl Acad Sci U S A. 2005; 102(28):9772-7. PMC: 1168955. DOI: 10.1073/pnas.0503279102. View

15.

Spiecker M, Liao J . Vascular protective effects of cytochrome p450 epoxygenase-derived eicosanoids. Arch Biochem Biophys. 2004; 433(2):413-20. DOI: 10.1016/j.abb.2004.10.009. View

16.

Exley M, Hand L, OShea D, Lynch L . Interplay between the immune system and adipose tissue in obesity. J Endocrinol. 2014; 223(2):R41-8. DOI: 10.1530/JOE-13-0516. View

17.

Harris R, Homma T, Jacobson H, Capdevila J . Epoxyeicosatrienoic acids activate Na+/H+ exchange and are mitogenic in cultured rat glomerular mesangial cells. J Cell Physiol. 1990; 144(3):429-37. DOI: 10.1002/jcp.1041440310. View

18.

Wang Z, Nakayama T . Inflammation, a link between obesity and cardiovascular disease. Mediators Inflamm. 2010; 2010:535918. PMC: 2929614. DOI: 10.1155/2010/535918. View

19.

Dieckmann S, Maurer S, Fromme T, Colson C, Virtanen K, Amri E . Fatty Acid Metabolite Profiling Reveals Oxylipins as Markers of Brown but Not Brite Adipose Tissue. Front Endocrinol (Lausanne). 2020; 11:73. PMC: 7046592. DOI: 10.3389/fendo.2020.00073. View

20.

Node K, Huo Y, Ruan X, Yang B, Spiecker M, Ley K . Anti-inflammatory properties of cytochrome P450 epoxygenase-derived eicosanoids. Science. 1999; 285(5431):1276-9. PMC: 2720027. DOI: 10.1126/science.285.5431.1276. View