J. Lipid Res.
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A more recent version of this article appeared on May 1, 2006

Papers In Press, published online ahead of print February 23, 2006
J. Lipid Res., doi:10.1194/jlr.M500414-JLR200
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Submitted on September 20, 2005
Revised on February 7, 2006
Accepted on February 23, 2006

Characterization of a new mouse model for human apoA-I/C-III/A-IV deficiency

Hafid Mezdour, Guilhem Larigauderie, Graciela Castro, Gerard Torpier, Jamila Fruchart, Maxime Nowak, Jean-charles Fruchart, Mustapha Rouis, and Nobuyo Maeda

Laboratoire de genetique experimentale, Institut Pasteur de Lille, Lille 59019

Corresponding Author: hafid.mezdour{at}pasteur-lille.fr

Human data raised the possibility that coronary heart disease (CHD) is associated with mutations in APOA1/C3/A4 gene cluster that result in multi-deficiency of cluster-encoded apolipoproteins and hypoalphalipoproteinemia. To test this hypothesis, we generated a mouse model for human apoA-I/C-III/A-IV deficiency. Homozygous mutants (Apoa1/c3/a4-/-), lacking the 3 cluster-encoded apolipoproteins, were viable and fertile. In addition, feeding behavior and growth were apparently normal. Total cholesterol, high-density lipoprotein cholesterol (HDLc), and triglycerides levels in the plasma of fasted mutants fed a regular chow were 32% (p<0.001), 17% (p<0.001) and 70% (p<0.01) those of wild type mice, respectively. When fed a high-fat Western-type (HFW) diet, Apoa1/c3/a4-/- mice showed a further drop in HDLc concentration and a moderate increase in TC, essentially in non-HDL fraction. The capacity of Apoa1/c3/a4-/- plasma to promote cholesterol efflux in vitro was decreased to 75% (p<0.001) and LCAT activity was decreased by 38% (p<0.01). Despite of the very low total plasma cholesterol, the imbalance in lipoprotein distribution caused small but detectable aortic lesions in one third of Apoa1/c3/a4-/- mice fed a HFW diet. In contrast, none of the wild type mice had lesions. These results demonstrate that Apoa1/c3/a4-/- mice display clinical features similar to human apoA-I/C-III/A-IV deficiency, i.e., marked hypoalphalipoproteinemia, and provide a further support for apoa1/c3/a4 gene cluster as a minor susceptibility locus for atherosclerosis in mice.


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