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 (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.
Köster
Anja
A
Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, Indiana 46225, USA. koester_anja@lilly.com
Chao
Y Bernice
YB
Mosior
Marian
M
Ford
Amy
A
Gonzalez-DeWhitt
Patricia A
PA
Hale
John E
JE
Li
Deshan
D
Qiu
Yubin
Y
Fraser
Christopher C
CC
Yang
Derek D
DD
Heuer
Josef G
JG
Jaskunas
S Richard
SR
Eacho
Patrick
P
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*
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