Abstract
Epoxide hydrolase 2 (EPHX2) is an emerging therapeutic target in several immunometabolic disorders. EPHX2 metabolizes anti-inflammatory epoxyeicosatrienoic acids into pro-inflammatory diols. The contribution of EPHX2 activity to human obesity remains unexplored. We compared the expression of EPHX2 between lean and obese humans (n = 20 each) in subcutaneous adipose tissue (SAT) and peripheral blood mononuclear cells (PBMCs) using RT-PCR, Western Blot analysis, immunohistochemistry, and confocal microscopy before and after a 3-month physical activity regimen. We also assessed EPHX2 levels during preadipocyte differentiation in humans and mice. EPHX2 mRNA and protein expression were significantly elevated in obese subjects, with concomitant elevated endoplasmic reticulum (ER) stress components (the 78-kDa glucose-regulated protein; GRP78, and the Activating transcription factor 6; ATF6) and inflammatory markers (Tumor necrosis factor-α; TNFα, and Interleukin 6; IL6) as compared to controls (p < 0.05). EPHX2 mRNA levels strongly correlated with adiposity markers. In obese individuals, physical activity attenuated EPHX2 expression levels in both the SAT and PBMCs, with a parallel decrease in ER stress and inflammation markers. EPHX2 expression was also elevated during differentiation of both human primary and 3T3-L1 mouse preadipocytes. Mediators of cellular stress (palmitate, homocysteine, and macrophage culture medium) also increased EPHX2 expression in 3T3-L1 preadipocytes. Our findings suggest that EPHX2 upregulation is linked to ER stress in adiposity and that physical activity may attenuate metabolic stress by reducing EPHX2 expression.
Highlights
Soluble epoxide hydrolase 2 (EPHX2), with dual epoxide hydrolase and lipid phosphatase activities, is an emerging therapeutic target in several diseases that share chronic metaflammation as the underlying cause [1]
With their action as immune cells, peripheral blood mononuclear cells (PBMCs) play a dynamic role in the crosstalk between adipose tissue and other organs in obesity [19]
We observed a correlation between obesity and the expression levels of the pro-inflammatory enzyme EPHX2 in adipose tissue and PBMCs in humans, findings supported by our in vivo results
Summary
Soluble epoxide hydrolase 2 (EPHX2), with dual epoxide hydrolase and lipid phosphatase activities, is an emerging therapeutic target in several diseases that share chronic metaflammation as the underlying cause [1]. One strategy for increasing the action of EETs involves decreasing the activity of EPHX2 [3]. EPHX2 plays further roles in glucose homeostasis, obesity, and diabetes, as shown in rodent and cell-line models [4]. Both the gene deletion and pharmacological inhibition of EPHX2 result in the preservation of islet cells in rodent models of type 1 diabetes and an increase in insulin sensitivity in type 2 diabetes (T2D) models, as does the direct administration of EETs [4]. A study in humans reported that the EPHX2(K55R) variant, which results in elevated EPHX2 activity, increases the risk of congenital heart disease in Caucasians [5]. The increased expression and activity of EPHX2 results in decreased EET levels and the EPHX2/EET pathway contributes to obesity and diabetes-induced endothelial dysfunction and cardiovascular disease [7]
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