Abstract
High plasma triglyceride (TG) levels and low HDL-C levels are risk factors for atherosclerosis and cardiovascular disease. Both plasma TG and HDL-C levels are regulated in part by the circulating inhibitor, angiopoietin-like 3 (ANGPTL3). ANGPTL3 inhibits the phospholipase, endothelial lipase (EL), which hydrolyzes the phospholipids of HDL, thus decreasing plasma HDL levels. ANGPTL3 also inhibits LPL, the lipase primarily responsible for the clearance of TGs from the circulation. Previous studies have shown that ANGPTL3 requires complex formation with the related ANGPTL protein, angiopoietin-like 8 (ANGPTL8), to efficiently inhibit LPL, but the role of ANGPTL8 in EL inhibition is not known. In this study, we characterized inhibition and binding of EL by ANGPTL3 and investigated the role of ANGPTL8 in EL inhibition. We found that inhibition of EL by ANGPTL3 was dose dependent and temperature dependent. Interestingly, this inhibition was diminished when EL was bound to endothelial cells or in the presence of heparin. Unlike previous findings with LPL, we found that ANGPTL8 did not significantly alter the binding or the inhibition of EL by ANGPTL3. In addition, we found that a common ANGPTL8 variant, which encodes an R59W mutation, altered the ability of ANGPTL3 to bind and inhibit LPL but not EL. Together, our data indicate that ANGPTL8 is not necessary for EL inhibition. We conclude that ANGPTL8 is specific for the regulation of TG-rich lipoproteins through the LPL pathway and that therapeutically targeting ANGPTL8 for the treatment of hypertriglyceridemia or cardiovascular disease may have different outcomes than targeting ANGPTL3.
Highlights
High plasma triglyceride (TG) levels and low HDL-C levels are risk factors for atherosclerosis and cardiovascular disease
Inhibition of endothelial lipase (EL) by angiopoietin-like 3 (ANGPTL3) The ability of ANGPTL3 to inhibit EL has been reported previously [18]. Consistent with these reports, when we incubated increasing concentrations of Streptagged ANGPTL3 with ∼10 μg/ml EL at 37◦C for 30 min, we found that ANGPTL3 was able to inhibit the phospholipase activity of EL in a dose-dependent of three independent experiments; each performed with biological duplicates
When EL was incubated with ANGPTL3 at 4◦C or 22◦C for 30 min and assayed for phospholipase activity, markedly less inhibition of phospholipase was observed compared with when EL and ANGPTL3 were incubated for 30 min at 37◦C before assaying activity (Fig. 2)
Summary
High plasma triglyceride (TG) levels and low HDL-C levels are risk factors for atherosclerosis and cardiovascular disease Both plasma TG and HDL-C levels are regulated in part by the circulating inhibitor, angiopoietin-like 3 (ANGPTL3). ANGPTL3 inhibits the phospholipase, endothelial lipase (EL), which hydrolyzes the phospholipids of HDL, decreasing plasma HDL levels. Angiopoietin-like 3 (ANGPTL3), angiopoietin-like 4 (ANGPTL4), and angiopoietin-like 8 (ANGPTL8) have all been shown to regulate plasma triglyceride (TG) levels through their inhibition of LPL [11,12,13,14,15,16,17]. Re-expression of ANGPTL3 in ANGPTL3-knockout mice increases plasma HDL-C levels [18] Together, these studies indicate that ANGPTL3 modulates HDL-C levels by targeting EL. It is not yet known if ANGPTL8 is required for, or modulates, the inhibition of EL by ANGPTL3
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