Background
Angiopoietin-likeProtein 3 (ANGPTL3) is a secreted glycoprotein that is structurally related to the angiopoietins. Mature mouse ANGPTL3 contains an N-terminalcoiled coil domain and a C-terminalfibrinogen-likedomain. Within the Nterminalfragment, mouse ANGPTL3 shares 83% and 92% aa sequence identity with human and rat ANGPTL3, respectively. ANGPTL3 is expressed in the liver from early in development through adulthood. ANGPTL3 directly inhibits lipoprotein lipase (LPL) and endothelial lipase (EL), enzymesresponsible for hydrolyzing circulating triglycerides and HDL phospholipids. This activity requires a putative heparin-bindingmotif which is N-terminalto thecoiled coil domain. Proteolytic removal of the fibrinogen-likedomain from the N-terminalfragment serves to activate ANGPTL3 and increase its ability toinhibit LPL in vitro and function in vivo. ANGPTL3 promotes an increase in circulating triglyceride levels without altering VLDL or HDL secretion oruptake. ANGPTL3 expression in vivo is up-regulatedby LXR agonists anddown-regulatedby insulin, leptin, and agonists of TRβ or PPARβ. ANGPTL3, secreted by fetal liver cells, also promotes the expansion of hematopoietic stem cells.
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