High plasma triglyceride (TG) levels and low HDL-C levels are risk factors for atherosclerosis and cardiovascular disease. Both plasma triglyceride 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 lipoprotein lipase (LPL), the lipase primarily responsible for the clearance of triglycerides from the circulation. Previous studies have shown that ANGPTL3 requires complex formation with the related angiopoietin-like 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- 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. Additionally, 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 triglyceride-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.

中文翻译：

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血管生成素样 3 对内皮脂肪酶的抑制不受血管生成素样 8 的调节。

高血浆甘油三酯 (TG) 水平和低 HDL-C 水平是动脉粥样硬化和心血管疾病的危险因素。血浆甘油三酯和 HDL-C 水平部分受循环抑制剂血管生成素样 3 (ANGPTL3) 的调节。ANGPTL3 抑制磷脂酶，即内皮脂肪酶 (EL)，它水解 HDL 的磷脂，从而降低血浆 HDL 水平。ANGPTL3 还抑制脂蛋白脂肪酶 (LPL)，该脂肪酶主要负责从循环中清除甘油三酯。先前的研究表明，ANGPTL3 需要与相关的血管生成素样蛋白、血管生成素样 8 (ANGPTL8) 形成复合物才能有效抑制 LPL，但 ANGPTL8 在 EL 抑制中的作用尚不清楚。在这项研究中，我们表征了 ANGPTL3 对 EL 的抑制和结合，并研究了 ANGPTL8 在 EL 抑制中的作用。我们发现 ANGPTL3 对 EL 的抑制是剂量和温度依赖性的。有趣的是，当 EL 与内皮细胞结合或存在肝素时，这种抑制作用会减弱。与之前的 LPL 发现不同，我们发现 ANGPTL8 并没有显着改变 ANGPTL3 对 EL 的结合或抑制。此外，我们发现编码 R59W 突变的常见 ANGPTL8 变体改变了 ANGPTL3 结合和抑制 LPL 而不是 EL 的能力。我们的数据一起表明 ANGPTL8 不是 EL 抑制所必需的。