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J. Biol. Chem., Vol. 283, Issue 4, 1839-1847, January 25, 2008

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Effect of Apolipoprotein M on High Density Lipoprotein Metabolism and Atherosclerosis in Low Density Lipoprotein Receptor Knock-out Mice^*

Christina Christoffersen¹, Matti Jauhiainen, Markus Moser^¶, Bo Porse, Christian Ehnholm, Michael Boesl^¶, Björn Dahlbäck^||, and Lars Bo Nielsen^**2

From the Department of Clinical Biochemistry, Rigshospitalet, and the ^**Department of Biomedical Sciences, University of Copenhagen, DK-2100 Copenhagen Denmark, the Department of Molecular Medicine, National Public Health Institute, Biomedicum, 00290, Helsinki, Finland, the ^¶Department of Molecular Medicine, Max Planck Institute of Biochemistry, 82152, Martinsried, Germany, and the ^||Department of Laboratory Medicine, Division of Clinical Chemistry, University of Lund, University Hospital, 20502, Malmö, Sweden

To investigate the role of apoM in high density lipoprotein (HDL) metabolism and atherogenesis, we generated human apoM transgenic (apoM-Tg) and apoM-deficient (apoM^–/–) mice. Plasma apoM was predominantly associated with 10–12-nm -migrating HDL particles. Human apoM overexpression (11-fold) increased plasma cholesterol concentration by 13–22%, whereas apoM deficiency decreased it by 17–21%. The size and charge of apoA-I-containing HDL in plasma were not changed in apoM-Tg or apoM^–/– mice. However, in plasma incubated at 37 °C, lecithin:cholesterol acyltransferase-dependent conversion of - to pre--migrating HDL was delayed in apoM-Tg mice. Moreover, lecithin: cholesterol acyltransferase-independent generation of pre-β-migrating apoA-I-containing particles in plasma was increased in apoM-Tg mice (4.2 ± 1.1%, p = 0.06) and decreased in apoM^–/– mice (0.5 ± 0.3%, p = 0.03) versus controls (1.8 ± 0.05%). In the setting of low density lipoprotein receptor deficiency, apoM-Tg mice with 2-fold increased plasma apoM concentrations developed smaller atherosclerotic lesions than controls. The effect of apoM on atherosclerosis may be facilitated by enzymatic modulation of plasma HDL particles, increased cholesterol efflux from foam cells, and an antioxidative effect of apoM-containing HDL.

Received for publication, June 4, 2007 , and in revised form, October 22, 2007.

^* This work was supported by Danish Heart Foundation Grants 02-1-2-24-22980 (to L. B. N.) and 06-4-B522-A918-22286 (to C. C.), Rigshospitalet, University of Copenhagen (to L. B. N.), Gerda and Aage Haensch's Foundation, Denmark (to C. C.), Sweden Research Council Grant 07143 and the Sweden Heart-Lung Foundation, Söderbergs Stiftelse, University Hospital in Malmö Foundation (to B. D.), Research Council for Health, Academy of Finland, Grant 114484 (to M. J.), the Finnish Foundation for Cardiovascular Research (to M. J.), and the Sigrid Juselius Foundation (to M. J. and C. E.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1–4 and Tables 1–3.

¹ To whom correspondence may be addressed: Dept. of Clinical Biochemistry, KB3011, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. Tel.: 45-3545-3011; Fax: 45-3545-2524; E-mail: Christina.christoffersen{at}rh.regionh.dk. ² To whom correspondence may be addressed: Dept. of Clinical Biochemistry, KB3011, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. Tel.: 45-3545-3011; Fax: 45-3545-2524; E-mail: larsbo{at}rh.dk.

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