Angiopoietin-like protein 3 (ANGPTL3) (ANGPTL3)

Angiopoietin-like protein 3 (ANGPTL3) is a hepatocyte-derived secretory protein that acts as a key regulator of plasma lipid levels by inhibiting lipoprotein lipase (LPL) and endothelial lipase (EL) [UniProt: P83751]. By suppressing these enzymes, ANGPTL3 hinders the hydrolysis of triglyceride-rich lipoproteins and the clearance of high-density lipoproteins, leading to elevated levels of circulating triglycerides and cholesterol [PubMed: 28538136]. Clinical interest in this protein intensified following the discovery that individuals with homozygous loss-of-function mutations in the ANGPTL3 gene exhibit significantly lower lipid levels and a reduced risk of coronary artery disease [PubMed: 20624548]. Consequently, ANGPTL3 has emerged as a therapeutic target for severe dyslipidemias, particularly in patients with homozygous familial hypercholesterolemia who are resistant to standard LDL receptor-targeted therapies [FDA: Evkeeza Label]. Current pharmacological approaches include the monoclonal antibody evinacumab, which neutralizes circulating ANGPTL3, and antisense or siRNA therapies that inhibit its production in the liver [PubMed: 33053283]. These treatments provide a potent lipid-lowering effect that operates independently of the LDL receptor pathway, offering a novel mechanism for cardiovascular risk reduction [PubMed: 32814437].

Other names

Angiopoietin-5ANG-5FHBL2Angiopoietin-related protein 3

ANGPTL3 inhibitors work by neutralizing the circulating protein or silencing its hepatic mRNA, thereby reversing its inhibitory effect on lipoprotein lipase (LPL) and endothelial lipase (EL), which enhances the clearance of triglycerides and other lipoproteins from the plasma [PubMed: 28538136, 32814437].