Loss-of-function variants in the ANGPTL3 gene are associated with markedly reduced plasma levels of all lipoproteins and a lower risk of developing atherosclerotic cardiovascular disease.
Does ANGPTL3 deficiency reduce plasma lipid levels and the risk of atherosclerotic cardiovascular disease?
Genetic ANGPTL3 deficiency leads to familial combined hypolipidemia and reduced ASCVD risk, providing a strong rationale for developing ANGPTL3-targeted lipid-lowering therapies.
Three members of the angiopoietin-like (ANGPTL) protein family-ANGPTL3, ANGPTL4 and ANGPTL8- are important regulators of plasma lipoproteins. They inhibit the enzyme lipoprotein lipase, which plays a key role in the intravascular lipolysis of triglycerides present in some lipoprotein classes. This review focuses on the role of ANGPTL3 as emerged from the study of genetic variants of Angptl3 gene in mice and humans. Both loss of function genetic variants and inactivation of Angptl3 gene in mice are associated with a marked reduction of plasma levels of triglyceride and cholesterol and an increased activity of lipoprotein lipase and endothelial lipase. In humans with ANGPTL3 deficiency, caused by homozygous loss of function (LOF) variants of Angptl3 gene, the levels of all plasma lipoproteins are greatly reduced. This plasma lipid disorder referred to as familial combined hypolipidemia (FHBL2) does not appear to be associated with distinct pathological manifestations. Heterozygous carriers of LOF variants have reduced plasma levels of total cholesterol and triglycerides and are at lower risk of developing atherosclerotic cardiovascular disease, as compared to non-carriers. These observations have paved the way to the development of strategies to reduce the plasma level of atherogenic lipoproteins in man by the inactivation of ANGPTL3, using either a specific monoclonal antibody or anti-sense oligonucleotides.
Tarugi et al. (2018) conducted a review in Familial combined hypolipidemia (FHBL2) and ANGPTL3 deficiency. ANGPTL3 loss of function genetic variants vs. Non-carriers was evaluated. Loss-of-function variants in the ANGPTL3 gene are associated with markedly reduced plasma levels of all lipoproteins and a lower risk of developing atherosclerotic cardiovascular disease.
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