Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, Affiliated to the Université de Montréal, Montréal, Québec, Canada.
PLoS One. 2012;7(7):e41865. doi: 10.1371/journal.pone.0041865. Epub 2012 Jul 27.
Proprotein convertase subtilisin/kexin-9 (PCSK9) enhances the degradation of hepatic low-density lipoprotein receptor (LDLR). Deletion of PCSK9, and loss-of-function mutants in humans result in lower levels of circulating LDL-cholesterol and a strong protection against coronary heart disease. Accordingly, the quest for PCSK9 inhibitors has major clinical implications. We have previously identified annexin A2 (AnxA2) as an endogenous binding partner and functional inhibitor of PCSK9. Herein, we studied the relevance of AnxA2 in PCSK9 inhibition and lipid metabolism in vivo. Plasma analyses of AnxA2(-/-) mice revealed: i) a ∼1.4-fold increase in LDL-cholesterol without significant changes in VLDLs or HDLs, and ii) a ∼2-fold increase in circulating PCSK9 levels. Western blotting and immunohistochemistry of AnxA2(-/-) tissues revealed that the LDLR was decreased by ∼50% in extrahepatic tissues, such as adrenals and colon. We also show that AnxA2-derived synthetic peptides block the PCSK9≡LDLR interaction in vitro, and adenoviral overexpression of AnxA2 in mouse liver increases LDLR protein levels in vivo. These results suggest that AnxA2 acts as an endogenous regulator of LDLR degradation, mostly in extrahepatic tissues. Finally, we identified an AnxA2 coding polymorphism, V98L, that correlates with lower circulating levels of PCSK9 thereby extending our results on the physiological role of AnxA2 in humans.
前蛋白转化酶枯草溶菌素 9（PCSK9）可增强肝脏低密度脂蛋白受体（LDLR）的降解。PCSK9 的缺失和人类中的功能丧失性突变会导致循环 LDL-胆固醇水平降低，并强烈预防冠心病。因此，寻找 PCSK9 抑制剂具有重要的临床意义。我们之前已经确定膜联蛋白 A2（AnxA2）是 PCSK9 的内源性结合伴侣和功能抑制剂。在此，我们研究了 AnxA2 在体内 PCSK9 抑制和脂代谢中的相关性。AnxA2（-/-）小鼠的血浆分析显示：i）LDL-胆固醇增加了约 1.4 倍，而 VLDL 或 HDL 没有明显变化，ii）循环 PCSK9 水平增加了约 2 倍。AnxA2（-/-）组织的 Western 印迹和免疫组化显示，LDLR 在肝外组织（如肾上腺和结肠）中减少了约 50%。我们还表明，AnxA2 衍生的合成肽在体外阻断 PCSK9≡LDLR 相互作用，并且在小鼠肝脏中过表达 AnxA2 会增加体内 LDLR 蛋白水平。这些结果表明，AnxA2 作为 LDLR 降解的内源性调节剂起作用，主要在肝外组织中起作用。最后，我们确定了一种 AnxA2 编码多态性 V98L，其与循环中较低的 PCSK9 水平相关，从而扩展了我们关于 AnxA2 在人类中生理作用的结果。
