Angptl4 upregulates cholesterol synthesis in liver via inhibition of LPL- and HL-dependent hepatic cholesterol uptake.
BACKGROUND
Dysregulation of plasma lipoprotein levels may increase the risk for atherosclerosis. Recently, angiopoietin-like protein 4, also known as fasting-induced adipose factor Fiaf, was uncovered as a novel modulator of plasma lipoprotein metabolism. Here we take advantage of the fasting-dependent phenotype of Angptl4-transgenic (Angptl4-Tg) mice to better characterize the metabolic function of Angptl4.


RESULTS
In 24-hour fasted mice, Angptl4 overexpression increased plasma triglycerides (TG) by 24-fold, which was attributable to elevated VLDL-, IDL/LDL- and HDL-TG content. Angptl4 overexpression decreased post-heparin LPL activity by stimulating conversion of endothelial-bound LPL dimers to circulating LPL monomers. In fasted but not fed state, Angptl4 overexpression severely impaired LPL-dependent plasma TG and cholesteryl ester clearance and subsequent uptake of fatty acids and cholesterol into tissues. Consequently, hepatic cholesterol content was significantly decreased, leading to universal upregulation of cholesterol and fatty acid synthesis pathways and increased rate of cholesterol synthesis.


CONCLUSIONS
The hypertriglyceridemic effect of Angptl4 is attributable to inhibition of LPL-dependent VLDL lipolysis by converting LPL dimers to monomers, and Angptl4 upregulates cholesterol synthesis in liver secondary to inhibition of LPL- and HL-dependent hepatic cholesterol uptake.
Lichtenstein
Laeticia
L
Nutrigenomics Consortium, TI Food and Nutrition, Wageningen, The Netherlands.
Berbée
Jimmy F P
JF
van Dijk
Susan J
SJ
van Dijk
Ko Willems
KW
Bensadoun
André
A
Kema
Ido P
IP
Voshol
Peter J
PJ
Müller
Michael
M
Rensen
Patrick C N
PC
Kersten
Sander
S
D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; D000818:Animals; D053898:Biosynthetic Pathways; D001786:Blood Glucose / Q000378:metabolism; D001798:Blood Proteins / Q000502:physiology*; D002784:Cholesterol / Q000096:biosynthesis* / Q000378:metabolism; D005215:Fasting / Q000378:metabolism; D005227:Fatty Acids / Q000096:biosynthesis*; D007333:Insulin Resistance / Q000502:physiology; D008066:Lipolysis / Q000502:physiology; D008071:Lipoprotein Lipase / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D014280:Triglycerides / Q000378:metabolism*
D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; C407088:Angptl4 protein, mouse; D001786:Blood Glucose; D001798:Blood Proteins; D005227:Fatty Acids; D014280:Triglycerides; D002784:Cholesterol; D008071:Lipoprotein Lipase