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

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 27; no. 11; pp. 2420 - 2427
• Main Authors: Lichtenstein, L.L, Berbee, J.F.P, Dijk, S.J, Willems van Dijk, K, Bensadoun, A, Kema, I.P, Voshol, P.J, Müller, M.R, Rensen, P.C.N, Kersten, S
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.11.2007; Hagerstown, MD Lippincott
• Subjects: Angiopoietin-like 4 Protein; angiopoietin-like protein-4; Angiopoietins; Animals; Associated diseases and complications; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Biosynthetic Pathways; Blood and lymphatic vessels; Blood Glucose - metabolism; Blood Proteins - physiology; Blood vessels and receptors; Cardiology. Vascular system; Cholesterol - biosynthesis; Cholesterol - metabolism; Diabetes. Impaired glucose tolerance; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Fasting - metabolism; Fatty Acids - biosynthesis; Fundamental and applied biological sciences. Psychology; hyperlipidemia; Insulin Resistance - physiology; insulin-resistance; lipase; lipid-metabolism; Lipolysis - physiology; Lipoprotein Lipase - metabolism; Liver - metabolism; Medical sciences; Mice; Mice, Transgenic; plasma; receptor; target gene; triglyceride-rich lipoproteins; Triglycerides - metabolism; Vertebrates: cardiovascular system; Digestive system; Enzyme; Liver; Lipids; Cardiovascular disease; Esterases; Lipoprotein lipase; triglycerides; Triglyceride; Angptl4; Uptake; Cholesterol; Carboxylic ester hydrolases; Vascular disease; Atherosclerosis; Hydrolases
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/ATVBAHA.107.151894

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.