The multi-faces of Angptl8 in health and disease: Novel functions beyond lipoprotein lipase modulation

Angiopoietin-like protein (ANGPTL) family members, mainly ANGPTL3, ANGPTL4 and ANGPTL8, are physiological inhibitors of lipoprotein lipase (LPL), and play a critical role in lipoprotein and triglyceride metabolism in response to nutritional cues. ANGPTL8 has been described by different names in various studies and has been ascribed various functions at the systemic and cellular levels. Circulating ANGPTL8 originates mainly from the liver and to a smaller extent from adipose tissues. In the blood, ANGPTL8 forms a complex with ANGPTL3 or ANGPTL4 to inhibit LPL in fed or fasted conditions, respectively. Evidence is emerging for additional intracellular and receptor-mediated functions of ANGPTL8, with implications in NFκB mediated inflammation, autophagy, adipogenesis, intra-cellular lipolysis and regulation of circadian clock. Elevated levels of plasma ANGPTL8 are associated with metabolic syndrome, type 2 diabetes, atherosclerosis, hypertension and NAFLD/NASH, even though the precise relationship is not known. Whether ANGPTL8 has direct pathogenic role in these diseases, remains to be explored. In this review, we develop a balanced view on the proposed association of this protein in the regulation of several pathophysiological processes. We also discuss the well-established functions of ANGPTL8 in lipoprotein metabolism in conjunction with the emerging novel extracellular and intracellular roles of ANGPTL8 and the implicated metabolic and signalling pathways. Understanding the diverse functions of ANGPTL8 in various tissues and metabolic states should unveil new opportunities of therapeutic intervention for cardiometabolic disorders.