Department of Medical Biosciences, Physiological Chemistry Umeå University, SE-901 87 Umeå, Sweden.
Biochem Biophys Res Commun. 2012 Aug 24;425(2):138-43. doi: 10.1016/j.bbrc.2012.07.048. Epub 2012 Jul 20.
Lipoprotein lipase (LPL) hydrolyzes triglycerides in plasma lipoproteins causing release of fatty acids for metabolic purposes in muscles and adipose tissue. LPL in macrophages in the artery wall may, however, promote foam cell formation and atherosclerosis. Angiopoietin-like protein (ANGPTL) 4 inactivates LPL and ANGPTL4 expression is controlled by peroxisome proliferator-activated receptors (PPAR). The mechanisms for inactivation of LPL by ANGPTL4 was studied in THP-1 macrophages where active LPL is associated with cell surfaces in a heparin-releasable form, while LPL in the culture medium is mostly inactive. The PPARδ agonist GW501516 had no effect on LPL mRNA, but increased ANGPTL4 mRNA and caused a marked reduction of the heparin-releasable LPL activity concomitantly with accumulation of inactive, monomeric LPL in the medium. Intracellular ANGPTL4 was monomeric, while dimers and tetramers of ANGPTL4 were present in the heparin-releasable fraction and medium. GW501516 caused an increase in the amount of ANGPTL4 oligomers on the cell surface that paralleled the decrease in LPL activity. Actinomycin D blocked the effects of GW501516 on ANGPTL4 oligomer formation and prevented the inactivation of LPL. Antibodies against ANGPTL4 interfered with the inactivation of LPL. We conclude that inactivation of LPL in THP-1 macrophages primarily occurs on the cell surface where oligomers of ANGPTL4 are formed.
脂蛋白脂肪酶（LPL）水解血浆脂蛋白中的甘油三酯，为肌肉和脂肪组织的代谢目的释放脂肪酸。然而，动脉壁中的巨噬细胞中的脂蛋白脂肪酶可能促进泡沫细胞的形成和动脉粥样硬化。血管生成素样蛋白（ANGPTL）4 使脂蛋白脂肪酶失活，ANGPTL4 的表达受过氧化物酶体增殖物激活受体（PPAR）控制。在 THP-1 巨噬细胞中研究了 ANGPTL4 使 LPL 失活的机制，其中活性 LPL 以肝素可释放的形式与细胞表面相关，而培养基中的 LPL 主要是无活性的。PPARδ激动剂 GW501516 对 LPL mRNA 没有影响，但增加了 ANGPTL4 mRNA，并导致肝素可释放的 LPL 活性显著降低，同时在培养基中积累了无活性的单体 LPL。细胞内的 ANGPTL4 是单体，而二聚体和四聚体的 ANGPTL4 存在于肝素可释放部分和培养基中。GW501516 增加了细胞表面 ANGPTL4 寡聚体的数量，与 LPL 活性的降低相平行。放线菌酮 D 阻断了 GW501516 对 ANGPTL4 寡聚体形成的影响，并阻止了 LPL 的失活。针对 ANGPTL4 的抗体干扰了 LPL 的失活。我们的结论是，THP-1 巨噬细胞中 LPL 的失活主要发生在形成 ANGPTL4 寡聚体的细胞表面。
