Angiopoietin-like protein 3 (ANGPTL3) is an important inhibitor of lipoprotein lipase and endothelial lipase that plays critical roles in lipoprotein metabolism. It specifically expresses in the liver and undergoes proprotein convertase-mediated cleavage during secretion, which generates an N-terminal coiled-coil domain and C-terminal fibrinogen-like domain that has been considered as the activation step for its function. Previous studies have reported that the polypeptide GalNAc-transferase GALNT2 mediates the O-glycosylation of the ANGPTL3 near the cleavage site, which inhibits the proprotein convertase (PC)-mediated cleavage in vitro and in cultured cells. However, loss-of-function mutation for GALNT2 has no effect on ANGPTL3 cleavage in human. Thus whether GALNT2 regulates the cleavage of ANGPTL3 in vivo is unclear. In present study, we systematically characterized the cleavage of Angptl3 in cultured cells and in vivo of mice. We found that endogenous Angptl3 is cleaved in primary hepatocytes and in vivo of mice, and this cleavage can be blocked by Galnt2 overexpression or PC inhibition. Moreover, suppressing galnt2 expression increases the cleavage of Angptl3 in mice dramatically. Thus, our results support the conclusion that Galnt2 is a key endogenous regulator for Angptl3 cleavage both in vitro and in vivo.

血管生成素样蛋白 3 (ANGPTL3) 是脂蛋白脂肪酶和内皮脂肪酶的重要抑制剂，在脂蛋白代谢中起关键作用。它在肝脏中特异性表达并在分泌过程中经历前蛋白转化酶介导的切割，产生 N 端卷曲螺旋结构域和 C 端纤维蛋白原样结构域，这被认为是其功能的激活步骤。以前的研究报道，多肽 GalNAc 转移酶 GALNT2 介导O-切割位点附近 ANGPTL3 的糖基化，可抑制体外和培养细胞中前蛋白转化酶 (PC) 介导的切割。然而，GALNT2 的功能丧失突变对人类中的 ANGPTL3 切割没有影响。因此，GALNT2 是否在体内调节 ANGPTL3 的切割尚不清楚。在本研究中，我们系统地表征了 Angptl3 在培养细胞和小鼠体内的裂解。我们发现内源性 Angptl3 在原代肝细胞和小鼠体内被切割，这种切割可以通过 Galnt2 过表达或 PC 抑制来阻断。此外，抑制galnt2表达会显着增加小鼠中 Angptl3 的裂解。因此，我们的结果支持以下结论：Galnt2 是体外和体内 Angptl3 切割的关键内源性调节剂。