Transgenic angiopoietin-like (Angptl)4 overexpression and targeted disruption of Angptl4 and Angptl3:: Regulation of triglyceride metabolism

Lipoprotein lipase (LPL) is a key regulator of triglyceride clearance. Its coordinated regulation during feeding and fasting is critical for maintaining lipid homeostasis and energy supply. Angiopoietin-like (Angpt1)3 and Angpt14 are secreted proteins that have been demonstrated to regulate triglyceride metabolism by inhibiting LPL. We have taken a targeted genetic approach to generate Angpt14- and Angpt13-deficient mice as well as transgenic mice overexpressing human Angpt14 in the liver. The Angpt14 transgenic mice displayed elevated plasma triglycerides and reduced postheparin plasma (PHP) LPL activity. A purified recombinant Angpt14 protein inhibited mouse LPL and recombinant human LPL activity in vitro. In contrast to the transgenic mice, Angpt14-deficient mice displayed hypotriglyceridemia and increased PHP LPL activity, with greater effects in the fasted compared with the fed state. Angpt13-deficient mice also displayed hypotriglyceridemia with elevated PHP LPL activity, but these mice showed a greater effect in the fed state. Mice deficient in both Angpt1 proteins showed an additive effect on plasma triglycerides and did not survive past 2 months of age. Our results show that Angpt13 and Angpt14 function to regulate circulating triglyceride levels during different nutritional states and therefore play a role in lipid metabolism during feeding/fasting through differential inhibition of LPL.