Angiopoietin-like protein 4 (ANGPTL4), N-terminal coiled-coil domain (ANGPTL4)

Angiopoietin-like protein 4 (ANGPTL4) is a secreted glycoprotein that serves as a key regulator of lipid metabolism by inhibiting the enzyme lipoprotein lipase (LPL) (PMC, 2019; PMC, 2025). The protein is composed of an N-terminal coiled-coil domain (nANGPTL4) and a C-terminal fibrinogen-like domain, with the N-terminal domain specifically mediating the inhibition of LPL (J Biol Chem, 2009; PMC, 2025). By suppressing LPL activity, the N-terminal domain of ANGPTL4 prevents the hydrolysis of triglycerides in circulating lipoproteins, leading to elevated plasma triglyceride levels (PMC, 2013). Genetic evidence, particularly the E40K loss-of-function variant, has demonstrated that reduced ANGPTL4 activity is strongly associated with lower triglycerides and a decreased risk of coronary artery disease (Arterioscler Thromb Vasc Biol, 2008; Lancet, 2025). This makes the N-terminal coiled-coil domain an attractive therapeutic target for the treatment of hypertriglyceridemia and the prevention of atherosclerotic cardiovascular disease (Lancet, 2025). Therapeutic agents currently in development, such as monoclonal antibodies (e.g., MAR001) and antisense oligonucleotides (e.g., Lipisense), aim to neutralize this domain to restore LPL activity and improve lipid profiles (Patsnap Synapse, 2024; Lancet, 2025). Although preclinical models initially suggested potential safety risks like mesenteric lymphadenopathy, human clinical data have shown that targeting this domain can safely and effectively lower lipids (PMC, 2016; Lancet, 2025). Beyond its metabolic role, ANGPTL4 is also involved in angiogenesis, vascular permeability, and glucose homeostasis, making it a multifaceted target in metabolic and cardiovascular medicine (PMC, 2019; PMC, 2025).

Other names

Angiopoietin-related protein 4Fasting-induced adipose factorFIAFHepatic fibrinogen/angiopoietin-related proteinHFARPPPAR-gamma angiopoietin-relatedPGARARP4nANGPTL4

Drugs targeting the N-terminal coiled-coil domain of ANGPTL4 act by inhibiting its ability to inactivate lipoprotein lipase (LPL). Monoclonal antibodies bind directly to the domain to prevent its interaction with LPL, while antisense oligonucleotides reduce the overall expression of the protein. By neutralizing the inhibitory effect of ANGPTL4, these therapies restore LPL activity, facilitating the clearance of triglyceride-rich lipoproteins and reducing plasma triglyceride and remnant cholesterol levels.