Effect of apolipoprotein M on HDL metabolism and atherosclerosis in LDL receptor knockout mice

doi:10.1074/jbc.M704576200

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Papers In Press, published online ahead of print November 15, 2007
J. Biol. Chem, 10.1074/jbc.M704576200
Submitted on June 4, 2007
Revised on October 22, 2007
Accepted on November 15, 2007

Effect of apolipoprotein M on HDL metabolism and atherosclerosis in LDL receptor knockout mice

Christina Christoffersen, Matti Jauhiainen, Markus Moser, Bo Porse, Christian Ehnholm, Michael Boesl, Björn Dahlbäck, and Lars Bo Nielsen

Clinical Biochemistry, Rigshospitalet, Copenhagen 2100

Corresponding Author: christina.christoffersen{at}rh.regionh.dk

To investigate the role of apoM in 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-sized a-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 37ºC, lecithin:cholesterol acyltransferase (LCAT)-dependent conversion of a- to prea-migrating HDL was delayed in apoM-Tg mice. Moreover, LCAT-independent generation of preß-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) vs. controls (1.8±0.05%). In the setting of LDL-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.

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