# Angiopoietin-like 3 monomers are abundant in human plasma but are unable to inhibit endothelial lipase

## TL;DR

ANGPTL3, a protein that regulates lipoproteins, is mostly found as monomers in blood, but these monomers cannot inhibit a key enzyme called endothelial lipase.

## Contribution

The study identifies a motif critical for ANGPTL3's function and shows that monomeric ANGPTL3 is more abundant than trimers in human plasma.

## Key findings

- A specific motif in ANGPTL3 is important for inhibiting endothelial lipase.
- Recombinant ANGPTL3 forms trimers, and disrupting trimerization prevents enzyme inhibition.
- Human plasma contains more monomeric ANGPTL3 than trimeric forms.

## Abstract

Angiopoietin-like 3 (ANGPTL3) is a major regulator of lipoprotein metabolism. ANGPTL3 deficiency results in lower levels of triglycerides, LDL-cholesterol (LDL-C), and HDL-cholesterol (HDL-C), and may protect from cardiovascular disease. ANGPTL3 oligomerizes with ANGPTL8 to inhibit lipoprotein lipase (LPL), the enzyme responsible for plasma triglyceride hydrolysis. Independently of ANGPTL8, oligomers of ANGPTL3 can inhibit endothelial lipase (EL), which regulates circulating HDL-C and LDL-C levels through the hydrolysis of lipoprotein phospholipids. The N-terminal region of ANGPTL3 is necessary for both oligomerization and lipase inhibition. However, our understanding of the specific residues that contribute to these functions is incomplete. In this study, we performed mutagenesis of the N-terminal region to identify residues important for EL inhibition and oligomerization. We also assessed the presence of different ANGPTL3 species in human plasma. We identified a motif important for lipase inhibition, and protein structure prediction suggested that this region interacted directly with EL. We also found that recombinant ANGPTL3 formed a homotrimer and was unable to inhibit EL activity when trimerization was disrupted. Surprisingly, we observed that human plasma contained more monomeric ANGPTL3 than trimeric ANGPTL3. An important implication of these findings is that previous correlations between circulating ANGPTL3 and circulating triglyceride-rich lipoproteins need to be revisited.

We find that ANGPTL3, a major regulator of lipoproteins, cannot inhibit endothelial lipase as a monomer, yet monomers are more abundant than trimers in circulation.