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.
Highlights
We investigated whether the PT activity or the epoxide hydrolase (EH) activity of Soluble epoxide hydrolase (sEH) participates in regulating expression of ATP‐binding cassette transporters‐A1 (ABCA1) upon Oxidized low‐density lipoprotein (oxLDL)
We identified a novel role of PT activity of sEH in cho‐ lesterol homeostasis during the transformation of macrophage foam cells
We first determined that sEH was significantly increased in atherosclerotic aortas and in particular, in intralesional macrophage foam cells
Summary
Soluble epoxide hydrolase (sEH), an enzyme with COOH‐terminal epoxide hydrolase (EH) and NH2‐terminal lipid phosphatase (PT) activities, is widely distributed in mammalian tissues and plays an important role in regulating multiple physiological functions.[1,2] The implication of hydrolase activity of sEH in the metabolism of epoxyeicosatrienoic acids (EETs), inflammation and hyperten‐ sion has been well documented.[3,4,5,6] For example, pharmacological inhibition of the EH activity of sEH or deletion of the sEH gene. | 6612 causes an increase in the accumulation of EETs and leads to the attenuation of angiotensin II–induced hypertension and cardiac hypertrophy and lipopolysaccharide‐induced inflammation in vitro and in vivo.[5,6,7,8] Oral administration with inhibitors targeting EH ac‐ tivity of sEH or genetic disruption of sEH significantly retards the progression of atherosclerosis in hyperlipidemic mouse models.[9,10] Multiple lines of evidence demonstrate that the PT domain of sEH has a crucial role in the regulation of cholesterol metabolism and cell growth in hepatocytes.[11,12] the sEH Glu287Arg mutant, which has reduced PT activity, is known to be a risk fac‐ tor for the development of coronary artery disease (CAD).[13,14] this sEH polymorphism is closely associated with the increase in plasma cholesterol and triglyceride in familial hyper‐ cholesterolaemia patients.[15] the role of the PT activity of sEH in the cholesterol metabolism of macrophage foam cells remains to be investigated. Our findings provide a novel explanation for the anti‐atherogenic properties of sEH and suggest a molecular target for the treatment of atherosclerosis
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