Furin Is the Primary in Vivo Convertase of Angiopoietin-like 3 and Endothelial Lipase in Hepatocytes
Furin Is the Primary in Vivo Convertase of Angiopoietin-like 3 and Endothelial Lipase in Hepatocytes
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DOI：
10.1074/jbc.m113.501304
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发表时间：
2013-09-13
影响因子：
4.8
通讯作者：
Seidah, Nabil G.
中科院分区：
文献类型：
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作者：
Essalmani, Rachid;Susan-Resiga, Delia;Seidah, Nabil G.
原蛋白转换酶(PC)Furin、PC5/6和PACE4具有独特和/或互补的功能。它们在小鼠体内的基因敲除(KO)导致了强烈而特异的表型，表明在体内，这些PC是独特的，在发育过程中是必不可少的。然而，它们也表现出多余的功能。肝血管生成素样3(Angptl3)通过与脂蛋白脂肪酶结合来抑制脂解作用。它在等离子体中以全长和截断的形式存在。后者更活跃，通过在类似呋喃的位置切割而产生。内皮脂肪酶(EL)与细胞表面的硫酸肝素蛋白多糖结合，催化高密度脂蛋白磷脂的水解。EL的活性受两种内源性抑制物Angptl3和ANGPTL4的调节，以及通过裂解释放N端催化和C端脂结合区来灭活EL的PC。在这里，由于Furin和PC5/6完全KO是致命的，我们使用了缺乏Furin或PC5/6的小鼠，特别是肝细胞(HKO)或完全缺乏PACE4的小鼠。在原代肝细胞中，Angptl3在细胞内仅被Furin处理成较短形式的Angptl3，在细胞外主要被PACE4处理。在体内，肝细胞中没有呋喃西林的影响与裂解的Angptl3的循环水平相似，而缺乏PACE4的影响很小。对原代肝细胞和体内EL加工的分析表明，它主要被Furin切割。然而，肝细胞中缺乏呋喃或PC5/6和完整的PACE4KO并不显著改变血浆高密度脂蛋白水平或EL活性。因此，抑制肝脏中的呋喃类药物不会改变血脂谱。
The proprotein convertases (PCs) furin, PC5/6, and PACE4 exhibit unique and/or complementary functions. Their knockout (KO) in mice resulted in strong and specific phenotypes demonstrating that, in vivo, these PCs are unique and essential during development. However, they also exhibit redundant functions. Liver angiopoietin-like 3 (ANGPTL3) inhibits lipolysis by binding to lipoprotein lipases. It is found in the plasma as full length and truncated forms. The latter is more active and generated by cleavage at a furin-like site. Endothelial lipase (EL) binds heparin sulfate proteoglycans on cell surfaces and catalyzes the hydrolysis of HDL phospholipids. EL activity is regulated by two endogenous inhibitors, ANGPTL3 and ANGPTL4, and by PCs that inactivate EL through cleavage releasing the N-terminal catalytic and C-terminal lipid-binding domains. Herein, because furin and PC5/6 complete KOs are lethal, we used mice lacking furin or PC5/6 specifically in hepatocytes (hKO) or mice completely lacking PACE4. In primary hepatocytes, ANGPTL3 was processed into a shorter form of ANGPTL3 intracellularly by furin only, and extracellularly mainly by PACE4. In vivo, the absence of furin in hepatocytes reduced by similar to 50% the circulating levels of cleaved ANGPTL3, while the lack of PACE4 had only a minor effect. Analysis of the EL processing in primary hepatocytes and in vivo revealed that it is mostly cleaved by furin. However, the lack of furin or PC5/6 in hepatocytes and complete PACE4 KO did not appreciably modify plasma HDL levels or EL activity. Thus, inhibition of furin in liver would not be expected to modify the plasma lipid profiles.