Department of Biochemistry and Molecular Biology, Fraternal Order of Eagles Diabetes Research Center, and Obesity Research and Education Initiative, University of Iowa, Iowa City, IA, USA.
Department of Biochemistry and Molecular Biology, Fraternal Order of Eagles Diabetes Research Center, and Obesity Research and Education Initiative, University of Iowa, Iowa City, IA, USA.
J Lipid Res. 2021;62:100112. doi: 10.1016/j.jlr.2021.100112. Epub 2021 Aug 27.
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.
高血浆甘油三酯 (TG) 水平和低高密度脂蛋白胆固醇 (HDL-C) 水平是动脉粥样硬化和心血管疾病的危险因素。血浆 TG 和 HDL-C 水平部分受循环抑制剂血管生成素样 3 (ANGPTL3) 调节。ANGPTL3 抑制磷脂酶、内皮脂肪酶 (EL)，后者水解 HDL 的磷脂，从而降低血浆 HDL 水平。ANGPTL3 还抑制 LPL，LPL 是主要负责从循环中清除 TG 的脂肪酶。先前的研究表明，ANGPTL3 需要与相关的血管生成素样蛋白 8 (ANGPTL8) 形成复合物，才能有效地抑制 LPL，但 ANGPTL8 在 EL 抑制中的作用尚不清楚。在这项研究中，我们对 EL 被 ANGPTL3 抑制和结合进行了表征，并研究了 ANGPTL8 在 EL 抑制中的作用。我们发现，ANGPTL3 对 EL 的抑制呈剂量依赖性和温度依赖性。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。与之前关于 LPL 的发现不同，我们发现 ANGPTL8 并没有显著改变 ANGPTL3 对 EL 的结合或抑制作用。此外，我们发现一个常见的 ANGPTL8 变体，它编码一个 R59W 突变，改变了 ANGPTL3 结合和抑制 LPL 的能力，但不改变 EL。总的来说，我们的数据表明 ANGPTL8 不是 EL 抑制所必需的。我们的结论是，ANGPTL8 是通过 LPL 途径调节富含 TG 的脂蛋白所必需的，而针对 ANGPTL8 治疗高甘油三酯血症或心血管疾病的治疗可能与针对 ANGPTL3 治疗的结果不同。
