Angiopoietin-like 3: An important protein in regulating lipoprotein levels

ANGPTL3 has emerged as a therapeutic target whose inhibition results in profound reductions of plasma lipids, including atherogenic triglyceride-rich lipoproteins and low-density lipoprotein cholesterol. The identification of ANGPTL3 deficiency as a cause of familial combined hypolipidemia in humans hastened the development of anti-ANGPTL3 therapeutic agents, including evinacumab (a monoclonal antibody inhibiting circulating ANGPTL3), vupanorsen (an antisense oligonucleotide [ASO] targeting hepatic ANGPTL3 mRNA for degradation), and others. Advances have also been made in ANGPTL3 vaccination and gene editing strategies, with the former still in preclinical phases and the latter in preparation for Phase 1 trials. Here, we review the discovery of ANGPTL3 as an important regulator of lipoprotein metabolism, molecular characteristics of the protein, mechanisms by which it regulates plasma lipids, and the clinical development of anti-ANGPTL3 agents. The clinical success of therapies inhibiting ANGPTL3 highlights the importance of this target as a novel approach in treating refractory hypertriglyceridemia and hypercholesterolemia.