Lactoferrin and its hydrolysate bind directly to the oleate-activated form of the lipolysis stimulated lipoprotein receptor
Lactoferrin and its hydrolysate bind directly to the oleate-activated form of the lipolysis stimulated lipoprotein receptor
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DOI：
10.1111/febs.12026
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发表时间：
2012-12-01
期刊：
影响因子：
5.4
通讯作者：
Corbier, Catherine
中科院分区：
文献类型：
--
作者：
Ahmad, Nazir;Girardet, Jean-Michel;Corbier, Catherine
在餐后阶段，肝脏清除富含甘油三酯的乳糜微粒是确定外周组织中膳食脂质生物利用度的重要一步。事实上，餐后脂血症升高通常与肥胖和冠心病风险增加有关。乳蛋白，乳铁蛋白，已被证明可以抑制肝脏乳糜微粒残留物的肝脏清除，导致餐后脂血增加。尽管对乳铁蛋白的潜在靶点进行了大量研究，但乳铁蛋白作用的分子机制仍不清楚。我们最近证实，脂解刺激的脂蛋白受体（LSR）有助于在餐后阶段去除富含甘油三酯的脂蛋白。在这里，我们报告说，虽然乳铁蛋白没有任何显着的影响LSR蛋白水平在小鼠Hepa 1 -6细胞，这种蛋白质与LSR共定位在细胞中，但只有在油酸的存在下，这是需要获得LSR在其作为脂蛋白受体的活性形式。使用纯化的LSR的配体印迹显示，乳铁蛋白在油酸存在下直接与受体结合，并阻止富含甘油三酯的脂蛋白的结合。乳铁蛋白的C叶和N叶以及由其水解衍生的肽的混合物都保留了以其活性形式结合LSR的能力。然后，我们提出，在体内乳铁蛋白治疗后观察到的餐后脂血升高部分是由其与游离脂肪酸活化的LSR的直接相互作用介导的，从而防止乳糜微粒及其残余物通过LSR途径清除。
The hepatic removal of triglyceride-rich chylomicrons during the postprandial phase represents an important step towards determining the bioavailability of dietary lipids amongst the peripheral tissues. Indeed, elevated postprandial lipemia is often associated with obesity and increased risk of coronary heart disease. The milk protein, lactoferrin, has been shown to inhibit hepatic chylomicron remnant removal by the liver, resulting in increased postprandial lipemia. Despite numerous studies on potential targets for lactoferrin, the molecular mechanisms underlying the effect of lactoferrin remain unclear. We recently demonstrated that the lipolysis stimulated lipoprotein receptor (LSR) contributes to the removal of triglyceride- rich lipoproteins during the postprandial phase. Here, we report that while lactoferrin does not have any significant effect on LSR protein levels in mouse Hepa1-6 cells, this protein colocalizes with LSR in cells but only in the presence of oleate, which is needed to obtain LSR in its active form as lipoprotein receptor. Ligand blotting using purified LSR revealed that lactoferrin binds directly to the receptor in the presence of oleate and prevents the binding of triglyceride-rich lipoproteins. Both C-and N-lobes of lactoferrin as well as a mixture of peptides derived from its hydrolysis retained the ability to bind LSR in its active form. We propose then that the elevated postprandial lipemia observed upon lactoferrin treatment in vivo is mediated in part by its direct interaction with free fatty acid activated LSR, thus preventing clearance of chylomicrons and their remnants through the LSR pathway.