Apolipoprotein C-III inhibits triglyceride hydrolysis by GPIHBP1-bound LPL
Apolipoprotein C-III inhibits triglyceride hydrolysis by GPIHBP1-bound LPL
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DOI：
10.1194/jlr.m078220
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发表时间：
2017-09-01
影响因子：
6.5
通讯作者：
Fong, Loren G.
中科院分区：
文献类型：
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作者：
Larsson, Mikael;Allan, Christopher M.;Fong, Loren G.
apoC-III通常被认为通过抑制LPL来延缓富含磷脂酰肌醇的脂蛋白（TRL）的血管内加工，但该观点主要基于对游离LPL的研究。我们现在认识到，血管内LPL既不是游离的，也不是松散结合的，而是与内皮细胞上的糖基磷脂酰肌醇锚定的HDL结合蛋白1（GPIHBP 1）紧密结合。在这里，我们重新审视了apoC-III对LPL的影响，重点是apoC-III影响GPIHBP 1结合的LPL活性的能力。我们发现APOC 3转基因小鼠的TRL在体外培养的细胞上与GPI-HBP 1结合的LPL正常结合，在体内与心脏毛细血管正常结合。然而，富含apoC-III的TRLs中的甘油三酯被游离LPL水解得更慢，并且当LPL与琼脂糖珠表面上的GPIHBP 1结合时，apoC-III对甘油三酯脂解的抑制作用被夸大。此外，重组apoC-III减少甘油三酯水解游离LPL只有温和的，但抑制作用更大时，LPL结合GPIHBP 1。与低血浆甘油三酯水平相关的突变体apoC-III（p.A23T）显示出抑制游离和GPIHBP 1结合LPL的能力降低。我们的研究结果表明，载脂蛋白C-III有效地抑制甘油三酯水解时，LPL结合GPIHBP 1。
apoC-III is often assumed to retard the intravascular processing of triglyceride-rich lipoproteins (TRLs) by inhibiting LPL, but that view is based largely on studies of free LPL. We now recognize that intravascular LPL is neither free nor loosely bound, but instead is tightly bound to glycosylphosphatidylinositol-anchored HDL-binding protein 1 (GPIHBP1) on endothelial cells. Here, we revisited the effects of apoC-III on LPL, focusing on apoC-III's capacity to affect the activity of GPIHBP1-bound LPL. We found that TRLs from APOC3 transgenic mice bound normally to GPI-HBP1-bound LPL on cultured cells in vitro and to heart capillaries in vivo. However, the triglycerides in apoC-III-enriched TRLs were hydrolyzed more slowly by free LPL, and the inhibitory effect of apoC-III on triglyceride lipolysis was exaggerated when LPL was bound to GPIHBP1 on the surface of agarose beads. Also, recombinant apoC-III reduced triglyceride hydrolysis by free LPL only modestly, but the inhibitory effect was greater when the LPL was bound to GPIHBP1. A mutant apoC-III associated with low plasma triglyceride levels (p. A23T) displayed a reduced capacity to inhibit free and GPIHBP1-bound LPL. Our results show that apoC-III potently inhibits triglyceride hydrolysis when LPL is bound to GPIHBP1.