title: Transgenic angiopoietin-like (angptl)4 overexpression and targeted disruption of angptl4 and angptl3: regulation of triglyceride metabolism.
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.
authors.affiliation: Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, Indiana 46225, USA. koester_anja@lilly.com
authors.forename: Anja
authors.initials: A
authors.lastname: Köster
authors.forename: Y Bernice
authors.initials: YB
authors.lastname: Chao
authors.forename: Marian
authors.initials: M
authors.lastname: Mosior
authors.forename: Amy
authors.initials: A
authors.lastname: Ford
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Gonzalez-DeWhitt
authors.forename: John E
authors.initials: JE
authors.lastname: Hale
authors.forename: Deshan
authors.initials: D
authors.lastname: Li
authors.forename: Yubin
authors.initials: Y
authors.lastname: Qiu
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Fraser
authors.forename: Derek D
authors.initials: DD
authors.lastname: Yang
authors.forename: Josef G
authors.initials: JG
authors.lastname: Heuer
authors.forename: S Richard
authors.initials: SR
authors.lastname: Jaskunas
authors.forename: Patrick
authors.initials: P
authors.lastname: Eacho
mesh_terms: D000091303:Angiopoietin-Like Protein 3; D000075803:Angiopoietin-Like Protein 4; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; D000818:Animals; D005215:Fasting / Q000097:blood; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D006949:Hyperlipidemias / Q000097:blood / Q000209:etiology; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008071:Lipoprotein Lipase / Q000037:antagonists & inhibitors / Q000097:blood; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019518:Postprandial Period; D011994:Recombinant Proteins / Q000494:pharmacology; D016019:Survival Analysis; D014280:Triglycerides / Q000097:blood*
chemical_list: C479896:ANGPTL3 protein, human; C474772:ANGPTL4 protein, human; D000091303:Angiopoietin-Like Protein 3; D000075803:Angiopoietin-Like Protein 4; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; D036341:Intercellular Signaling Peptides and Proteins; D011994:Recombinant Proteins; D014280:Triglycerides; D006493:Heparin; D008071:Lipoprotein Lipase