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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:969.)
© 2009 American Heart Association, Inc.

Clinical and Population Studies

Caloric Restriction and Exercise Increase Plasma ANGPTL4 Levels in Humans via Elevated Free Fatty Acids

Sander Kersten; Laeticia Lichtenstein; Emma Steenbergen; Karin Mudde; Henk F.J. Hendriks; Matthijs K. Hesselink; Patrick Schrauwen; Michael Müller

From the Nutrigenomics Consortium (S.K., L.L., P.S., M.M.), TI Food and Nutrition, Wageningen, The Netherlands; Nutrition, Metabolism, and Genomics Group, Division of Human Nutrition (S.K., L.L., E.S., K.M., M.M.), Wageningen University, The Netherlands; Business Unit Biosciences (H.F.J.H.), TNO Quality of Life, Zeist, The Netherlands; and the Department of Human Movement Sciences (M.K.H.) and the Department of Human Biology (P.S.), Maastricht University, The Netherlands.

Correspondence to Sander Kersten, PhD, Nutrition, Metabolism, and Genomics Group, Wageningen University, Bomenweg 2, 6703 HD Wageningen, The Netherlands. E-mail sander.kersten{at}wur.nl

Objective— Plasma lipoprotein levels are determined by the balance between lipoprotein production and clearance. Recently, angiopoietin-like protein 4 (ANGPTL4) was uncovered as a novel endocrine factor that potently raises plasma triglyceride levels by inhibiting triglyceride clearance. However, very little is known about ANGPTL4 in human. Here we set out to identify physiological determinants of plasma ANGPTL4 levels in humans, focusing on the effect of energy restriction and plasma FFAs.

Methods and Results— We developed an ELISA for quantitative measurement of ANGPTL4 in human plasma. Using this assay we found major variations in baseline plasma ANGPTL4 levels between individuals. Within an individual, plasma ANGPTL4 levels remain stable throughout the day but increase significantly in response to long-term fasting, chronic caloric restriction, and endurance exercise. Intralipid injection as well as treatment with a β-adrenergic agonist, both of which lead to elevated plasma FFA levels, increased plasma ANGPTL4 levels compared to control treatment. Fatty acids markedly induced ANGPTL4 gene expression in rat hepatoma FAO cells, human primary myocytes, and mouse intestinal MSIE cells.

Conclusion— In conclusion, our results show that plasma ANGPTL4 levels are increased by fasting, caloric restriction, and exercise, which is likely mediated by elevated plasma FFAs.

ANGPTL4 raises plasma triglycerides by inhibiting their clearance. Very little is known about ANGPTL4 in human. We developed an ELISA to quantitatively measure plasma ANGPTL4 in numerous human interventions. We show that plasma ANGPTL4 levels are increased by fasting, caloric restriction, and exercise, probably via elevated plasma FFAs.

Key Words: ANGPTL4 • free fatty acids • caloric restriction