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Papers In Press, published online ahead of print October 1, 2007
J. Lipid Res., doi:10.1194/jlr.M700009-JLR200

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Journal of Lipid Research, Vol. 48, 2182-2192, October 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

The Hyplip2 locus causes hypertriglyceridemia by decreased clearance of triglycerides

Corina J. A. Moen^1,*, Aart P. Tholens^*, Peter J. Voshol^,, Willeke de Haan, Louis M. Havekes^,,**,, Peter Gargalovic, Aldons J. Lusis, Ko Willems van Dk^*,,**, Rune R. Frants^*, Marten H. Hofker^***, and Patrick C. N. Rensen^,,**

^* Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands
Netherlands Organization for Applied Scientific Research Quality of Life, Gaubius Laboratory, Leiden, The Netherlands
^** Department of General Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands
Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands
Departments of Microbiology, Immunology, and Molecular Genetics; Medicine; and Human Genetics, University of California Los Angeles, Los Angeles, CA
^*** Department of Molecular Genetics, University Maastricht, Maastricht, The Netherlands
Department of Pathology and Laboratory Medicine, University Medical Center Groningen, Groningen, The Netherlands

The online version of this article (available at http://www.jlr.org) contains supplementary data in the form of one Table.

Published, JLR Papers in Press, July 3, 2007.

¹ To whom correspondence should be addressed. e-mail: cmoen{at}lumc.nl

The Hyplip2 congenic mouse strain contains part of chromosome 15 from MRL/MpJ on the BALB/cJ background. Hyplip2 mice show increased plasma levels of cholesterol and predominantly triglycerides (TGs) and are susceptible to diet-induced atherosclerosis. This study aimed at elucidation of the mechanism(s) explaining the hypertriglyceridemia. Hypertriglyceridemia can result from increased intestinal or hepatic TG production and/or by decreased LPL-mediated TG clearance. The intestinal TG absorption and chylomicron formation were studied after intravenous injection of Triton WR1339 and an intragastric load of olive oil containing glycerol tri[³H]oleate. No difference was found in intestinal TG absorption. Moreover, the hepatic VLDL-TG production rate and VLDL particle production, after injection of Triton WR1339, were also not affected. To investigate the LPL-mediated TG clearance, mice were injected intravenously with glycerol tri[³H]oleate-labeled VLDL-like emulsion particles. In Hyplip2 mice, the particles were cleared at a decreased rate (half-life of 25 ± 6 vs. 11 ± 2 min; P < 0.05) concomitant with a decreased uptake of emulsion TG-derived ³H-labeled fatty acids by the liver and white adipose tissue. The increased plasma TG levels in Hyplip2 mice do not result from an enhanced intestinal absorption or increased hepatic VLDL production but are caused by decreased LPL-mediated TG clearance.

Supplementary key words congenic mice • lipoproteins • lipoprotein lipase • triglyceride hydrolysis • lipoprotein clearance

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