Angiopoietin like protein 3 regulates low-density lipoprotein transport through aortic endothelial cells via endothelial lipase

Angiopoietin-like protein 3 (ANGPTL3) inhibits endothelial lipase (EL, encoded by LIPG) and lipoprotein lipase (LPL) and has emerged as a promising target for lipid-lowering therapies. While ANGPTL3 inhibition lowers circulating triglycerides and low-density lipoprotein cholesterol (LDL-C), its impact on atherosclerotic cardiovascular disease (ASCVD) remains uncertain. This study investigates the roles of ANGPTL3 and EL in the trans-endothelial transport of LDL and high-density lipoprotein (HDL), an early step in atherogenesis. Using primary human aortic endothelial cells (HAEC), we demonstrate that EL promotes binding, uptake, and transcytosis of LDL and HDL, with its catalytic activity being essential for transport but not for surface association. ANGPTL3 selectively reduced the transport of LDL but not HDL through HAEC. Mechanistically, EL and scavenger receptor BI (SR-BI) act sequentially to mediate LDL uptake, but independently of each other towards HDL uptake. Ex vivo, ANGPTL3 reduced LDL accumulation within bovine aorta. Interestingly, ANGPTL4 had no measurable effect on lipoprotein transport, while ANGPTL8 modestly inhibited both LDL and HDL association with endothelial cells. Our findings provide evidence that ANGPTL3 inhibits EL-mediated transendothelial LDL transport. Opposing effects of ANGPTL3 inhibition on LDL-C concentration and LDL entry into the arterial wall may explain why recent population studies did not reveal any genetically causal association of ANGPTL3 and LIPG with ASCVD risk.