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Submitted on April 21, 2005
Accepted on July 27, 2005
Lilly Research Laboratories, Eli Lilly and Company, 355 E. Merrill Street, Indianapolis, IN 46285, USA (A.K., Y.B.C, M.M., A. F., P.A.G., J.E.H., D.L., D.D.Y., J.G.H., S.R.J., P.E.) and Millennium Pharmaceutical Inc., 35 Landsdowne St., Cambridge, MA 02139, USA (Y.Q., C.C.F.)
* To whom correspondence should be addressed. E-mail: koester_anja{at}lilly.com.
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 3 (Angptl3) and angiopoietin-like 4 (Angptl4) are secreted proteins that have been demonstrated to regulate triglyceride metabolism by inhibiting LPL. We have taken a targeted genetic approach to generate Angptl4 and Angptl3-deficient mice, as well as transgenic mice over-expressing human Angptl4 in the liver. The Angptl4 transgenic mice displayed elevated plasma triglycerides and reduced post-heparin plasma (PHP) LPL activity. A purified recombinant Angptl4 protein inhibited mouse LPL and recombinant human LPL activity in vitro. In contrast to the transgenic mice, Angptl4-deficient mice displayed hypotriglyceridemia and increased PHP LPL activity, with greater effects in the fasted compared with the fed state. Angptl3-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 angiopoeitin-like proteins showed an additive effect on plasma triglycerides and did not survive past 2 months of age. Our results show that Angptl3 and Angptl4 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.
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