The phosphatase activity of soluble epoxide hydrolase regulates ATP‐binding cassette transporter‐A1‐dependent cholesterol efflux

Abstract

The contribution of soluble epoxide hydrolase (sEH) to atherosclerosis has been well defined. However, less is understood about the role of sEH and its underlying mechanism in the cholesterol metabolism of macrophages. The expression of sEH protein was increased in atherosclerotic aortas of apolipoprotein E‐deficient mice, primarily in macrophage foam cells. Oxidized low‐density lipoprotein (oxLDL) increased sEH expression in macrophages. Genetic deletion of sEH (sEH−/−) in macrophages markedly exacerbated oxLDL‐induced lipid accumulation and decreased the expression of ATP‐binding cassette transporters‐A1 (ABCA1) and apolipoprotein AI‐dependent cholesterol efflux following oxLDL treatment. The down‐regulation of ABCA1 in sEH−/− macrophages was due to an increase in the turnover rate of ABCA1 protein but not in mRNA transcription. Inhibition of phosphatase activity, but not hydrolase activity, of sEH decreased ABCA1 expression and cholesterol efflux following oxLDL challenge, which resulted in increased cholesterol accumulation. Additionally, oxLDL increased the phosphatase activity, promoted the sEH‐ABCA1 complex formation and decreased the phosphorylated level of ABCA1 at threonine residues. Overexpression of phosphatase domain of sEH abrogated the oxLDL‐induced ABCA1 phosphorylation and further increased ABCA1 expression and cholesterol efflux, leading to the attenuation of oxLDL‐induced cholesterol accumulation. Our findings suggest that the phosphatase domain of sEH plays a crucial role in the cholesterol metabolism of macrophages.

Deletion of soluble epoxide hydrolase suppressed chronic kidney disease-related vascular calcification by restoring Sirtuin 3 expression

“…Beside the famous effect of EETs hydrolysis, sEH are also able to directly interact with proteins like Akt and AMP-activated protein kinase (AMPK) [ 10 , 20 , 21 ]. In this study, we revealed that sEH may be able to associate with Sirt3 under high Pi condition.…”

CRISPR/Cas9-mediated inactivation of the phosphatase activity of soluble epoxide hydrolase prevents obesity and cardiac ischemic injury

“…1 a), which are other bioactive phospholipid mediators, to monoacylglycerol (MAGs) [8] , [9] , [10] , [11] . In addition, in vitro cellular works suggested a complementary role of sEH-H and sEH-P activities in the regulation of metabolic or vascular homeostasis [12] , [13] , [14] , [15] . While recombinant mice that do not express ephx2 have been around for some time [16] , [17] , they do not allow to specifically studying sEH-P because both activities are eliminated.…”

Curcumin promotes cholesterol efflux by regulating ABCA1 expression through miR-125a-5p/SIRT6 axis in THP-1 macrophage to prevent atherosclerosis

“…The inflammatory response initiated by lipid-laden macrophages and the regulation of cholesterol metabolism is inevitable to the initiation and progression of AS (Lien et al, 2019). An increased macrophage cholesterol efflux was proven to significantly and inversely associate with cardiovascular diseases (Wang et al, 2018).…”