Nilsson Stefan K, Anderson Fredrick, Ericsson Madelene, Larsson Mikael, Makoveichuk Elena, Lookene Aivar, Heeren Joerg, Olivecrona Gunilla
Department of Medical Biosciences/Physiological Chemistry, Umeå University, SE-901 87 Umeå, Sweden.
Biochim Biophys Acta. 2012 Oct;1821(10):1370-8. doi: 10.1016/j.bbalip.2012.06.003. Epub 2012 Jun 21.
Lipoprotein lipase (LPL) is important for clearance of triacylglycerols (TG) from plasma both as an enzyme and as a bridging factor between lipoproteins and receptors for endocytosis. The amount of LPL at the luminal side of the capillary endothelium determines to what extent lipids are taken up. Mechanisms to control both the activity of LPL and its transport to the endothelial sites are regulated, but poorly understood. Angiopoietin-like proteins (ANGPTLs) 3 and 4 are potential control proteins for LPL, but plasma concentrations of ANGPTLs do not correlate with plasma TG levels. We investigated the effects of recombinant human N-terminal (NT) ANGPTLs3 and 4 on LPL-mediated bridging of TG-rich lipoproteins to primary mouse hepatocytes and found that the NT-ANGPTLs, in concentrations sufficient to cause inactivation of LPL in vitro, were unable to prevent LPL-mediated lipoprotein uptake. We therefore investigated the effects of lipoproteins (chylomicrons, VLDL and LDL) on the inactivation of LPL in vitro by NT-ANGPTLs3 and 4 and found that LPL activity was protected by TG-rich lipoproteins. In vivo, postprandial TG protected LPL from inactivation by recombinant NT-ANGPTL4 injected to mice. We conclude that lipoprotein-bound LPL is stabilized against inactivation by ANGPTLs. The levels of ANGPTLs found in blood may not be sufficient to overcome this stabilization. Therefore it is likely that the prime site of action of ANGPTLs on LPL is in subendothelial compartments where TG-rich lipoprotein concentration is lower than in blood. This could explain why the plasma levels of TG and ANGPTLs do not correlate.
脂蛋白脂肪酶（LPL）作为一种酶以及脂蛋白与内吞作用受体之间的桥梁因子，对于从血浆中清除三酰甘油（TG）至关重要。毛细血管内皮腔侧的LPL量决定了脂质的摄取程度。控制LPL活性及其向内皮部位转运的机制受到调节，但了解甚少。血管生成素样蛋白（ANGPTL）3和4是LPL的潜在调控蛋白，但ANGPTL的血浆浓度与血浆TG水平不相关。我们研究了重组人N端（NT）ANGPTL3和4对LPL介导的富含TG的脂蛋白与原代小鼠肝细胞桥接的影响，发现浓度足以在体外使LPL失活的NT-ANGPTL无法阻止LPL介导的脂蛋白摄取。因此，我们研究了脂蛋白（乳糜微粒、极低密度脂蛋白和低密度脂蛋白）对NT-ANGPTL3和4体外使LPL失活的影响，发现富含TG的脂蛋白可保护LPL活性。在体内，餐后TG可保护LPL免受注射给小鼠的重组NT-ANGPTL4的失活作用。我们得出结论，与脂蛋白结合的LPL对ANGPTL介导的失活具有稳定作用。血液中发现的ANGPTL水平可能不足以克服这种稳定作用。因此，ANGPTL对LPL的主要作用位点可能位于内皮下隔室，其中富含TG的脂蛋白浓度低于血液中的浓度。这可以解释为什么TG和ANGPTL的血浆水平不相关。
