ANGPTL3
Description
The ANGPTL3 (angiopoietin like 3) is a protein-coding gene located on chromosome 1.
Angiopoietin-like 3 (ANGPTL3) is a protein encoded by the ANGPTL3 gene in humans. It is a member of the angiopoietin-like family of secreted factors and is primarily expressed in the liver. ANGPTL3 has the characteristic structure of angiopoietins, consisting of a signal peptide, N-terminal coiled-coil domain, and the C-terminal fibrinogen (FBN)-like domain. The FBN-like domain in ANGPTL3 binds to alpha-5/beta-3 integrins, inducing endothelial cell adhesion and migration. ANGPTL3 is a dual inhibitor of lipoprotein lipase (LPL) and endothelial lipase (EL), leading to increased plasma triglyceride, LDL cholesterol, and HDL cholesterol levels. It inhibits endothelial lipase hydrolysis of HDL-phospholipid (PL), increasing HDL-PL levels. ANGPTL3 plays a significant role in promoting the uptake of circulating triglycerides into white adipose tissue during the fed state. This process may be activated by Angptl8, a feeding-induced hepatokine, to inhibit postprandial LPL activity in cardiac and skeletal muscles. In humans, ANGPTL3 is a determinant factor of HDL level and positively correlates with plasma HDL cholesterol.
ANGPTL3 acts as a hepatokine, regulating lipid and glucose metabolism. It influences the trafficking of energy substrates to storage or oxidative tissues in response to food intake. ANGPTL3 increases plasma triglycerides by suppressing their clearance through inhibiting lipoprotein lipase (LPL) activity. This inhibition is indirect, involving recruitment of PCSK6 and FURIN to LPL, leading to its cleavage and dissociation from the cell surface. This function does not require ANGPTL3 proteolytic cleavage but seems to be mediated by the N-terminal domain and is not inhibited by GPIHBP1. ANGPTL3 can also inhibit endothelial lipase, resulting in increased plasma levels of high density lipoprotein (HDL) cholesterol and phospholipids. It binds to adipocytes, activating lipolysis and releasing free fatty acids and glycerol. ANGPTL3 specifically suppresses LPL in oxidative tissues, routing very low density lipoprotein (VLDL)-TG to white adipose tissue (WAT) for storage in response to food intake. This function may involve cooperation with circulating, liver-derived ANGPTL8 and ANGPTL4 expression in WAT. ANGPTL3 contributes to lower plasma levels of low density lipoprotein (LDL)-cholesterol by a mechanism independent of the canonical pathway involving APOE and LDLR. It may stimulate hypothalamic LPL activity.
ANGPTL3 is also known as ANG-5, ANGPT5, ANL3, FHBL2.
