ANGPTL3

ANGPTL3 (angiopoietin-like protein 3) is a liver-derived secreted protein that functions as a central regulator of plasma lipid metabolism through inhibition of lipoprotein lipase (LPL) and endothelial lipase (EL), thereby controlling triglyceride-rich lipoprotein processing and systemic lipid homeostasis^[1][2]. Mechanistically, ANGPTL3 participates in the ANGPTL3-ANGPTL4-ANGPTL8 regulatory axis, which coordinates tissue-specific triglyceride trafficking according to nutritional status by modulating LPL activity in cardiac muscle, skeletal muscle, and adipose tissue^[3]. ANGPTL8 enhances the ability of ANGPTL3 to bind and inhibit LPL, whereas ANGPTL4 primarily regulates LPL activity through tissue-dependent and nutritional-state-dependent mechanisms, establishing complementary but distinct functions within this pathway^[3][4]. In human genetics and disease studies, loss-of-function variants in ANGPTL3 are associated with markedly reduced plasma triglyceride, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) concentrations, supporting a critical role in lipoprotein metabolism and atherosclerotic cardiovascular disease risk modulation^[2][1]. Compared with related isoforms, ANGPTL3 is predominantly expressed in the liver and exerts broader effects on multiple lipoprotein fractions, whereas ANGPTL4 displays stronger tissue-specific regulation and ANGPTL8 functions mainly as a cofactor that potentiates ANGPTL3-mediated LPL inhibition^[3][4]. Therefore, ANGPTL3 has emerged as a prominent therapeutic target, and monoclonal antibodies as well as antisense oligonucleotide approaches have demonstrated activation of LPL and substantial reductions in circulating triglyceride-rich lipoproteins in preclinical and clinical studies^[2][5].