ANGPTL8

ANGPTL8 is an atypical member of the angiopoietin-like protein family that lacks the C-terminal fibrinogen-like domain and is predominantly expressed in the liver under nutritional and hormonal regulation^[1][2]. Mechanistically, ANGPTL8 functions as a key regulator of triglyceride trafficking by forming complexes with ANGPTL3 and ANGPTL4, thereby modulating lipoprotein lipase (LPL) activity in feeding and fasting states^[1][3][4]. Through this ANGPTL3-ANGPTL4-ANGPTL8 regulatory axis, ANGPTL8 directs fatty acid partitioning between adipose and oxidative tissues and contributes to systemic lipid homeostasis^[3][4][5]. Emerging evidence further indicates that ANGPTL8 participates in intracellular signaling pathways linked to NF-κB-mediated inflammation, autophagy, adipogenesis, intracellular lipolysis, and circadian regulation, extending its biological functions beyond LPL inhibition^[1]. In metabolic disease settings, circulating ANGPTL8 levels are altered in obesity, metabolic syndrome, type 2 diabetes, atherosclerosis, hypertension, and nonalcoholic fatty liver disease, supporting its relevance as a biomarker and mechanistic target in cardiometabolic research^[1][2]. Compared with related isoforms such as ANGPTL3 and ANGPTL4, ANGPTL8 lacks the fibrinogen-like domain and primarily acts through protein-complex formation rather than independent lipase inhibition, highlighting its distinct regulatory role within the ANGPTL family^[2][4]. For experimental applications, genetic and antibody-based modulation of ANGPTL8 has been used to investigate triglyceride metabolism and LPL regulation, supporting ongoing efforts to develop lipid-lowering therapeutic strategies targeting the ANGPTL3-ANGPTL8 pathway^[5].