Research Article
Angiopoietin-like 3 inhibition of endothelial lipase is not modulated by angiopoietin-like 8

https://doi.org/10.1016/j.jlr.2021.100112Get rights and content
Under a Creative Commons license
open access

Abstract

High plasma triglyceride (TG) levels and low HDL-C levels are risk factors for atherosclerosis and cardiovascular disease. Both plasma TG and HDL-C levels are regulated in part by the circulating inhibitor, angiopoietin-like 3 (ANGPTL3). ANGPTL3 inhibits the phospholipase, endothelial lipase (EL), which hydrolyzes the phospholipids of HDL, thus decreasing plasma HDL levels. ANGPTL3 also inhibits LPL, the lipase primarily responsible for the clearance of TGs from the circulation. Previous studies have shown that ANGPTL3 requires complex formation with the related ANGPTL protein, angiopoietin-like 8 (ANGPTL8), to efficiently inhibit LPL, but the role of ANGPTL8 in EL inhibition is not known. In this study, we characterized inhibition and binding of EL by ANGPTL3 and investigated the role of ANGPTL8 in EL inhibition. We found that inhibition of EL by ANGPTL3 was dose dependent and temperature dependent. Interestingly, this inhibition was diminished when EL was bound to endothelial cells or in the presence of heparin. Unlike previous findings with LPL, we found that ANGPTL8 did not significantly alter the binding or the inhibition of EL by ANGPTL3. In addition, we found that a common ANGPTL8 variant, which encodes an R59W mutation, altered the ability of ANGPTL3 to bind and inhibit LPL but not EL. Together, our data indicate that ANGPTL8 is not necessary for EL inhibition. We conclude that ANGPTL8 is specific for the regulation of TG-rich lipoproteins through the LPL pathway and that therapeutically targeting ANGPTL8 for the treatment of hypertriglyceridemia or cardiovascular disease may have different outcomes than targeting ANGPTL3.

Supplementary key words

endothelial lipase
lipoprotein lipase
HDL
lipoprotein metabolism
endothelial cells
angiopoietin-like proteins
ANGPTL3
ANGPTL8
triglycerides
cardiovascular disease

Abbreviations

ANGPTL
angiopoietin like
ANGPTL3
angiopoietin-like 3
ANGPTL8
angiopoietin-like 8
cDNA
complementary DNA
CHO
Chinese hamster ovary
EL
endothelial lipase
HEK 293T
human embryonic kidney 293T cells
HSPG
heparan sulfate proteoglycan
TG
triglyceride
RHMVEC
rat heart microvessel endothelial cell

Cited by (0)