LRP5 and plasma cholesterol levels modulate the canonical Wnt pathway in peripheral blood leukocytes
LRP5 and plasma cholesterol levels modulate the canonical Wnt pathway in peripheral blood leukocytes
复制标题
DOI：
10.1038/icb.2015.41
复制
发表时间：
2015-08-01
影响因子：
4
通讯作者：
Badimon, Lina
中科院分区：
文献类型：
--
作者：
Borrell-Pages, Maria;Carolina Romero, July;Badimon, Lina
炎症是在入侵或受伤后触发的，以恢复体内平衡。虽然Wnt/β-catenin信号的激活是对细胞损伤的最早的分子反应之一，但它在炎症中的作用仍然不清楚。我们的假设是低密度脂蛋白(LDL)受体相关蛋白5(LRP5)和典型的Wnt信号通路是炎症机制的调节器。野生型(WT)和LRP5(-/-)小鼠被喂以高胆固醇(HC)饮食，以引发血脂和慢性炎症。日粮中添加植物甾醇酯(PSES)以诱导低密度脂蛋白胆固醇降低和炎症减轻。HC WT小鼠的血清胆固醇水平升高，与LRP5和Wnt/β-catenin基因表达增加相关，而在HC LRP5(-/-)小鼠中，Wnt/β-catenin途径被关闭。在功能上，HC诱导了LRP5(-/-)小鼠的促炎基因表达，提示Wnt途径在炎症中具有抑制作用。饮食PSE可降低WT和LRP5(-/-)小鼠的血清胆固醇水平。此外，在WT小鼠中，PSE增加了抗炎基因的表达，并抑制了Wnt/β-catenin的激活。WT小鼠饲喂HC后，肝脏Vldlr、Lrp2和LRP6基因表达增加，而LRP5(-/-)小鼠肝脏Vldlr、Lrp2和LRP6基因表达增加，提示这些受体在清除血浆脂蛋白中起作用。最后，LRP5的抗动脉粥样硬化作用被证明是因为HC LRP5(-/-)小鼠比WT小鼠发生了更大的动脉粥样硬化病变。我们的结果表明，LRP5和Wnt信号通路在外周血白细胞中具有抗炎、促进生存的作用。
Inflammation is triggered after invasion or injury to restore homeostasis. Although the activation of Wnt/beta-catenin signaling is one of the first molecular responses to cellular damage, its role in inflammation is still unclear. It was our hypothesis that the low-density lipoprotein (LDL) receptor-related protein 5 (LRP5) and the canonical Wnt signaling pathway are modulators of inflammatory mechanisms. Wild-type (WT) and LRP5(-/-) mice were fed a hypercholesterolemic (HC) diet to trigger dislipidemia and chronic inflammation. Diets were supplemented with plant sterol esters (PSEs) to induce LDL cholesterol lowering and the reduction of inflammation. HC WT mice showed increased serum cholesterol levels that correlated with increased Lrp5 and Wnt/beta-catenin gene expression while in the HC LRP5(-/-) mice Wnt/beta-catenin pathway was shut down. Functionally, HC induced pro-inflammatory gene expression in LRP5(-/-) mice, suggesting an inhibitory role of the Wnt pathway in inflammation. Dietary PSE administration downregulated serum cholesterol levels in WT and LRP5(-/-) mice. Furthermore, in WT mice PSE increased anti-inflammatory genes expression and inhibited Wnt/beta-catenin activation. Hepatic gene expression of Vldlr, Lrp2 and Lrp6 was increased after HC feeding in WT mice but not in LRP5(-/-) mice, suggesting a role for these receptors in the clearance of plasmatic lipoproteins. Finally, an antiatherogenic role for LRP5 was demonstrated as HC LRP5(-/-) mice developed larger aortic atherosclerotic lesions than WT mice. Our results show an anti-inflammatory, pro-survival role for LRP5 and the Wnt signaling pathway in peripheral blood leukocytes.