Angiopoietin-like protein 4 converts lipoprotein lipase to inactive monomers and modulates lipase activity in adipose tissue
Angiopoietin-like protein 4 converts lipoprotein lipase to inactive monomers and modulates lipase activity in adipose tissue
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DOI：
10.1073/pnas.0604026103
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发表时间：
2006-11-14
影响因子：
11.1
通讯作者：
Olivecrona, Gunilla
中科院分区：
文献类型：
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作者：
Sukonina, Valentina;Lookene, Aivar;Olivecrona, Gunilla
脂蛋白脂肪酶 (LPL) 在脂蛋白代谢中发挥着核心作用，可维持血液中正常的脂蛋白水平，并通过其活性的组织特异性调节，确定甘油三酯何时以及在哪些组织中被卸载。最近的数据表明，血管生成素样蛋白 (Angptl)-4 抑制 LPL 并延缓脂蛋白分解代谢。我们在此证明 Angptl-4 的 N 端卷曲螺旋结构域与 LPL 短暂结合，并且相互作用导致酶从催化活性二聚体转化为无活性但仍折叠的单体，对肝素的亲和力降低。当 Angptl-4 与 LPL 的摩尔比小于等摩尔比时，就会发生失活，其强烈依赖于温度，并且不会消耗 Angptl-4。此外，我们发现大鼠脂肪组织中的 Angptl-4 mRNA 快速变化，并且在进食到禁食和禁食到进食的转变过程中，Angptl-4 mRNA 丰度的变化与 LPL 活性呈负相关。我们得出的结论是，Angptl-4 是脂肪组织中禁食诱导的 LPL 控制器，以一种不寻常的方式在细胞外作用于天然构象，就像一个展开的分子伴侣。
Lipoprotein lipase (LPL) has a central role in lipoprotein metabolism to maintain normal lipoprotein levels in blood and, through tissue specific regulation of its activity, to determine when and in what tissues triglycerides are unloaded. Recent data indicate that angiopoietin-like protein (Angptl)-4 inhibits LPL and retards lipoprotein catabolism. We demonstrate here that the N-terminal coiled-coil domain of Angptl-4 binds transiently to LPL and that the interaction results in conversion of the enzyme from catalytically active dimers to inactive, but still folded, monomers with decreased affinity for heparin. Inactivation occurred with less than equimolar ratios of Angptl-4 to LPL, was strongly temperature-dependent, and did not consume the Angptl-4. Furthermore, we show that Angptl-4 mRNA in rat adipose tissue turns over rapidly and that changes in the Angptl-4 mRNA abundance are inversely correlated to LPL activity, both during the fed-to-fasted and fasted-to-fed transitions. We conclude that Angptl-4 is a fasting-induced controller of LPL in adipose tissue, acting extracellularly on the native conformation in an unusual fashion, like an unfolding molecular chaperone.