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

Anja Köster, Y. Bernice Chao, Marian Mosior, Amy Ford, Patricia A. Gonzalez-DeWhitt, John E. Hale, Deshan Li, Yubin Qiu, Christopher C. Fraser, Derek D. Yang, Josef G. Heuer, S. Richard Jaskunas, Patrick Eacho

Research output: Contribution to journalArticlepeer-review

341 Scopus citations

Abstract

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 (Angptl)3 and 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 overexpressing human Angptl4 in the liver. The Angptl4 transgenic mice displayed elevated plasma triglycerides and reduced postheparin 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 Angptl 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.

Original languageEnglish
Pages (from-to)4943-4950
Number of pages8
JournalEndocrinology
Volume146
Issue number11
DOIs
StatePublished - Nov 2005
Externally publishedYes

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