Furin Is the Primary in Vivo Convertase of Angiopoietin-like 3 and Endothelial Lipase in Hepatocytes

Abstract

Background: Proprotein convertases (PCs) activate overexpressed endothelial lipase (EL) inhibitor angiopoietin-like-3 (ANGPTL3) and inactivate EL. Results: In PC knock-out-mice, analysis of primary hepatocytes and circulating ANGPTL3 and EL fragments revealed that furin is their primary convertase. Conclusion: However, the lack of hepatocyte furin had no major impact on HDL-cholesterol or EL phospholipase activity. Significance: Inhibition/silencing of furin in hepatocytes would not affect lipid profiles.

Proprotein convertase furin regulates osteocalcin and bone endocrine function

“…Consistent with the possibility that it may play an important role in osteoblasts, furin was detected in primary osteoblasts at comparable or higher levels than those observed in hepatocytes, thymus, and MIN6 β cells, where this enzyme is known to have nonredundant functions ( Figure 2G) (22)(23)(24). We therefore next assessed the requirement for furin in pro-OCN maturation in osteoblasts.…”

“…Furin was shown to be essential for the maintenance of peripheral immune tolerance through its expression in T lymphocytes (24), to play a role in the granular acidification of pancreatic β cells (23), and to be required for cardiac development through its expression in endothelial cells (38). In contrast, studies of furin functions in liver showed that it might act redundantly with other PCs in this tissue (22,30). In the present study, we show that furin is the cognate PC for pro-OCN activation in osteoblasts, providing genuine in vivo evidence for a nonredundant role of furin in this cell type.…”

Proprotein convertase furin/PCSK3 and atherosclerosis: New insights and potential therapeutic targets

“…In line with these results, the N-terminal fragments cannot be detected in furin-absent mice, suggesting that furin plays a crucial role in EL inactivation by cleavage. Moreover, human EL cleavage is achieved exclusively by furin both extracellularly (30%) and intracellularly (70%) [16]. EL activity can be regulated by two endogenous inhibitors, angiopoietin-like protein (ANGPTL) 3 and 4.…”

“…The transfection of a plasmid expressing murine ANGPTL3 into HEK293 cells which stably express EL results in the inhibition of~60% EL activity. In primary hepatocytes, it was shown that ANGPTL3 can only be cleavage-activated intracellularly by furin and extracellularly by furin and PACE4 [16]. In vivo, hepatic furin absence decreased approximately 50% cleaved ANGPTL3 levels in plasma, indicating that furin may also negatively influence EL activity through ANGPTL3 [16].…”

“…In primary hepatocytes, it was shown that ANGPTL3 can only be cleavage-activated intracellularly by furin and extracellularly by furin and PACE4 [16]. In vivo, hepatic furin absence decreased approximately 50% cleaved ANGPTL3 levels in plasma, indicating that furin may also negatively influence EL activity through ANGPTL3 [16]. Since EL can remodel the plasma high-density lipoprotein (HDL) particles through its phospholipase activity and promote the elimination of proatherogenic lipoproteins, including chylomicron remnants and LDL, furin-mediated EL inactivation may aggravate atherosclerosis by reducing the apoB-containing lipoprotein levels in the plasma.…”