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, angiopoietinlike 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 Angpt14-transgenic (Angpt14Tg) mice to better characterize the metabolic function of Angpt14. Methods and Results-In 24-hour fasted mice, Angpt14 overexpression increased plasma triglycerides (TG) by 24-fold, which was attributable to elevated VLDL-, IDL/ LDL-and HDL-TG content. Angpt14 overexpression decreased post-heparin LPL activity by stimulating conversion of endothelial-bound LPL dimers to circulating LPL monomers. In fasted but not fed state, Angpt14 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 Angpt14 is attributable to inhibition of LPL-dependent VLDL lipolysis by converting LPL dimers to monomers, and Angpt14 upregulates cholesterol synthesis in liver secondary to inhibition of LPL-and HL-dependent hepatic cholesterol uptake.