Ploug Michael
Finsen Laboratory, Rigshospitalet.
Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.
Curr Opin Lipidol. 2022 Apr 1;33(2):112-119. doi: 10.1097/MOL.0000000000000800.
Lipoprotein lipase (LPL) is the rate-limiting enzyme for intravascular processing of circulating triglyceride-rich lipoproteins (TRLs). One emerging strategy for therapeutic lowering of plasma triglyceride levels aims at increasing the longevity of LPL activity by attenuating its inhibition from angiopoietin-like proteins (ANGPTL) 3, 4 and 8. This mini-review focuses on recent insights into the molecular mechanisms underpinning the regulation of LPL activity in the intravascular unit by ANGPTLs with special emphasis on ANGPTL4.
Our knowledge on the molecular interplays between LPL, its endothelial transporter GPIHBP1, and its inhibitor(s) ANGPTL4, ANGPTL3 and ANGPTL8 have advanced considerably in the last 2 years and provides an outlined on how these proteins regulate the activity and compartmentalization of LPL. A decisive determinant instigating this control is the inherent protein instability of LPL at normal body temperature, a property that is reciprocally impacted by the binding of GPIHBP1 and ANGPTLs. Additional layers in this complex LPL regulation is provided by the different modulation of ANGPTL4 and ANGPTL3 activities by ANGPTL8 and the inhibition of ANGPTL3/8 complexes by apolipoprotein A5 (APOA5).
Posttranslational regulation of LPL activity in the intravascular space is essential for the differential partitioning of TRLs across tissues and their lipolytic processing in response to nutritional cues.
脂蛋白脂肪酶（LPL）是循环中富含甘油三酯的脂蛋白（TRL）血管内代谢的限速酶。一种新出现的降低血浆甘油三酯水平的治疗策略旨在通过减弱血管生成素样蛋白（ANGPTL）3、4和8对LPL活性的抑制作用来延长LPL活性的持续时间。本综述聚焦于ANGPTL对血管内单元中LPL活性调控的分子机制的最新见解，特别强调ANGPTL4。
在过去两年中，我们对LPL、其内皮转运蛋白GPIHBP1及其抑制剂ANGPTL4、ANGPTL3和ANGPTL8之间分子相互作用的认识有了显著进展，并概述了这些蛋白如何调节LPL的活性和分布。促使这种调控的一个决定性因素是LPL在正常体温下固有的蛋白质不稳定性，这一特性会受到GPIHBP1和ANGPTL结合的反向影响。ANGPTL8对ANGPTL4和ANGPTL3活性的不同调节以及载脂蛋白A5（APOA5）对ANGPTL3/8复合物的抑制为这种复杂的LPL调节增加了额外层次。
血管内空间中LPL活性的翻译后调控对于TRL在不同组织间的分配及其响应营养信号的脂解过程至关重要。
