Abstract
Genetic and clinical studies have demonstrated that loss-of-function variants in the angiopoietin-like 3 (ANGPTL3) gene are associated with decreased plasma levels of triglycerides (TGs), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C), which leads to a significant reduction in cardiovascular risk. For this reason, ANGPTL3 is considered an important new pharmacological target for the treatment of cardiovascular diseases (CVDs) together with more conventional lipid lowering therapies, such as statins and anti proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies. Experimental evidence demonstrates that anti-ANGPTL3 therapies have an important anti-atherosclerotic effect. Results from phase I clinical trials with a monoclonal anti-ANGPTL3 antibody (evinacumab) and anti-sense oligonucleotide (ASO) clearly show a significant lipid lowering effect. In addition, from the analysis of the protein structure of ANGPTL3, it has been hypothesized that, beyond its inhibitory activity on lipoprotein and endothelial lipases, this molecule may have a pro-inflammatory, pro-angiogenic effect and a negative effect on cholesterol efflux, implying additional pro-atherosclerotic properties. In the future, data from phase II clinical trials and additional experimental evidence will help to define the efficacy and the additional anti-atherosclerotic properties of anti-ANGPTL3 therapies beyond the already available lipid lowering therapies.
Highlights
Since its discovery in 1999 by Conklin and colleagues [1], angiopoietin-like 3 (ANGPTL3) has been considered a very potent modulator of triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) plasma levels by inhibiting lipoprotein lipase (LPL) [2–4] and endotelial lipase (EL) activities [5]
It was observed that individuals with loss-of-function (LOF) mutations (Table 1) in the ANGPTL3 gene were affected by familial combined hypolipidemia (FHBL2) and characterized by very low levels of apolipoprotein B, apolipoprotein A1 and their associated lipoproteins -very low-density lipoprotein (VLDL), LDL and HDL respectively compared to non-carriers [7–9]
These subjects were protected from cardiovascular events, making ANGPTL3 an important pharmacological target for reducing cardiovascular risk, especially for homozygous familial hypercholesterolemic (HoFH) patients, where statins and mAb anti-proprotein convertase subtilisin/kexin type 9 (PCSK9) are not effective [10]
Summary
Since its discovery in 1999 by Conklin and colleagues [1], angiopoietin-like 3 (ANGPTL3) has been considered a very potent modulator of triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) plasma levels by inhibiting lipoprotein lipase (LPL) [2–4] and endotelial lipase (EL) activities [5]. Its effect on lipid metabolism was originally identified in a subgroup of inbred strain KK obese mice (name derived from Kondo Keiichi subsequently renamed KK/San strain) [6], expressing a truncated form of ANGPTL3 that was associated with hyperinsulinemia and hyperglycemia. These data indicate that TG levels are positively correlated with a loss of activity of ANGPTL3 [2]
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