Targeting angiopoietin-like 3 (ANGPTL3) in atherosclerosis: from bench to bedside.

Atherosclerotic cardiovascular disease (ASCVD) is the largest cause of morbidity and mortality worldwide. Lipid-lowering therapies are the current major cornerstone of ASCVD management. Statins, ezetimibe, fibrates, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors effectively reduce plasma low-density lipoprotein cholesterol (LDL-C) level in most individuals at risk of atherosclerosis. Still, some patients (such as those with homozygous familial hypercholesterolemia), who did not respond to standard therapies, and some patients who cannot take these agents remain at a high risk of ASCVD. Recent years have witnessed tremendous progress in understanding the mechanism and efficacy of lipid-lowering strategies. Apart from the recently approved PCSK9 and ATP citrate lyase (ACLY) inhibitors, angiopoietin-like 3 (ANGPTL3) is another potential target for the treatment of dyslipidemia and its clinical sequalae-atherosclerosis. ANGPTL3 is a pivotal modulator of plasma triglycerides (TG), LDL-C, and high-density lipoprotein cholesterol (HDL-C) levels achieved by inhibiting the activities of lipoprotein lipase (LPL) and endothelial lipase (EL). Familial combined hypolipidemia is derived from the ANGPTL3 loss-of-function (LOF) mutations, which leads to low levels of LDL-C, HDL-C, and TG and has a 34 percent decreased risk of ASCVD compared with non-carriers. To date, monoclonal antibodies (evinacumab) and antisense oligonucleotides against ANGPTL3 have been investigated in clinical trials for dyslipidemia therapy. Herein, we reviewed the biology and function of ANGPTL3, as well as the latest developments of ANGPTL3 targeted therapies. We also summarized evidence from basic research to clinical trials, with an aim to provide novel insights into biological functions of ANGPTL3 and related targeted therapies. This article is protected by copyright. All rights reserved.