title: Angptl4 upregulates cholesterol synthesis in liver via inhibition of LPL- and HL-dependent hepatic cholesterol uptake.
abstract: 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.
authors.affiliation: Nutrigenomics Consortium, TI Food and Nutrition, Wageningen, The Netherlands.
authors.forename: Laeticia
authors.initials: L
authors.lastname: Lichtenstein
authors.forename: Jimmy F P
authors.initials: JF
authors.lastname: Berbée
authors.forename: Susan J
authors.initials: SJ
authors.lastname: van Dijk
authors.forename: Ko Willems
authors.initials: KW
authors.lastname: van Dijk
authors.forename: André
authors.initials: A
authors.lastname: Bensadoun
authors.forename: Ido P
authors.initials: IP
authors.lastname: Kema
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Voshol
authors.forename: Michael
authors.initials: M
authors.lastname: Müller
authors.forename: Patrick C N
authors.initials: PC
authors.lastname: Rensen
authors.forename: Sander
authors.initials: S
authors.lastname: Kersten
mesh_terms: 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*
chemical_list: 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