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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:2420.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Angptl4 Upregulates Cholesterol Synthesis in Liver via Inhibition of LPL- and HL-Dependent Hepatic Cholesterol Uptake

Laeticia Lichtenstein; Jimmy F.P. Berbée; Susan J. van Dijk; Ko Willems van Dijk; André Bensadoun; Ido P. Kema; Peter J. Voshol; Michael Müller; Patrick C.N. Rensen; Sander Kersten

From the Nutrigenomics Consortium (L.L., K.W.v.D., M.M., S.K.), TI Food and Nutrition, Wageningen, the Netherlands; Nutrition, Metabolism, and Genomics group (L.L., S.J.v.D., M.M., S.K.), Wageningen University, Wageningen, the Netherlands; the Departments of General Internal Medicine (J.F.P.B., K.W.v.D., P.C.N.R.), Endocrinology and Metabolic Diseases (J.F.P.B., P.J.V., P.C.N.R.), and Human Genetics (K.W.v.D.), Leiden University Medical Center, Leiden, the Netherlands; the Division of Nutritional Sciences (A.B.), Cornell University, Ithaca, NY; and Pathology and Laboratory Medicine (I.P.K.), University Medical Center Groningen, Groningen, the Netherlands.

Correspondence to Sander Kersten, PhD, Nutrition, Metabolism, and Genomics group, Wageningen University, PO BOX 8129, 6700EV Wageningen The Netherlands. E-mail sander.kersten{at}wur.nl

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.

Methods and 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.

The present study exploits the fasting-dependent phenotype of Angptl4-transgenic mice to characterize the function of Angptl4. We conclude that: (1) Angptl4 causes hypertriglyceridemia by inhibiting LPL-dependent VLDL lipolysis by converting LPL dimers to monomers, and (2) Angptl4 upregulates hepatic cholesterol synthesis secondary to inhibition of LPL- and HL-dependent hepatic cholesterol uptake.

Key Words: Angptl4 • lipoprotein lipase • cholesterol • triglycerides • liver