Seven proteins have been identified to contain a coiled-coil domain and a fibrinogen-like domain similar to those found in angiopoietins, and have been therefore designated angiopoietin-like proteins (ANGPTLs; angiopoietin-related proteins). While ANGPTLs do not bind to angiopoietin receptors Tie1 and/or Tie2, different ANGPTLs have been identifi ed as regulators of angiogenesis. However, at least three ANGPTLs have been found to be regulators of metabolism. ANGPTL3 importance for lipid metabolism was first indicated by the genetic analysis of a mutant strain of obese mice with low plasma lipid levels. Administration of recombinant ANGPTL3 (angiopoietin-5) to ANGPTL3-defi cient mice as well as wild type mice increased the plasma levels of free fatty acid (NEFA), triacylglycerol (TG) and cholesterol. ANGPTL3 decreases plasma TG clearance by inhibiting lipoprotein lipase (LPL), and activates lipolysis upon direct binding to adipocytes. Next to LPL, ANGPTL3 also suppresses endothelial lipase (EL) thereby regulating high-density lipoprotein (HDL). In liver, ANGPTL3 has been shown to be cleaved and activated by proprotein convertases. The effect of ANGPTL6 (angiopoietin-related growth factor (AGF)) on metabolism has been revealed by studying ANGPTL6-deficient mice. Surviving mice developed marked obesity, lipid metabolic disorders, and insulin resistance accompanied by reduced energy expenditure. In contrast, transgenic ANGPTL6-mice are lean and more insulin-sensitive despite their normal energy intake and serum leptin levels. ANGPTL6 has also been found to suppress gluconeogenesis through an Akt/FocO1-dependent pathway.
