J. Lipid Res. Neurobiology of Lipids (ISSN1683-5506)
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Originally published In Press as doi:10.1194/jlr.M500414-JLR200 on February 23, 2006

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Journal of Lipid Research, Vol. 47, 912-920, May 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

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

Hafid Mezdour*,1, Guilhem Larigauderie{dagger}, Graciela Castro{dagger}, Gerard Torpier{dagger}, Jamila Fruchart{dagger}, Maxime Nowak{dagger}, Jean-Charles Fruchart{dagger}, Mustapha Rouis{dagger} and Nobuyo Maeda§

* Laboratoire de Génétique Expérimentale, Institut Pasteur de Lille, 59019 Lille, France
{dagger} Institut National de la Santé et de la Recherche Médicale U-545, Institut Pasteur de Lille, 59019 Lille, France
§ Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7525

Published, JLR Papers in Press, February 23, 2006.

1 To whom correspondence should be addressed. e-mail: hafid.mezdour{at}pasteur-lille.fr

Human data raised the possibility that coronary heart disease is associated with mutations in the apolipoprotein gene cluster APOA1/C3/A4 that result in multideficiency of cluster-encoded apolipoproteins and hypoalphalipoproteinemia. To test this hypothesis, we generated a mouse model for human apolipoprotein A-I (apoA-I)/C-III/A-IV deficiency. Homozygous mutants (Apoa1/c3/a4–/–) lacking the three cluster-encoded apolipoproteins were viable and fertile. In addition, feeding behavior and growth were apparently normal. Total cholesterol (TC), high density lipoprotein cholesterol (HDLc), and triglyceride 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), respectively, those of wild-type mice. When fed a high-fat Western-type (HFW) diet, Apoa1/c3/a4–/– mice showed a further decrease 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 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 further support for the apoa1/c3/a4 gene cluster as a minor susceptibility locus for atherosclerosis in mice.

Supplementary key words apoa1/c3/a4 gene cluster (mouse) • APOA1/C3/A4 gene cluster (human) • knockout mouse • hypoalphalipoproteinemia • high-fat Western-type diet • atherosclerosis

Abbreviations: APOA1/C3/A4, apolipoprotein gene cluster (human); apoa1/c3/a4, apolipoprotein gene cluster (mouse); Apoa1/c3/a4+/+ and Apoa1/c3/a4–/–, gene cluster wild-type (+/+ or Aca+/+) and knockout (–/– or Aca–/–) mice, respectively; HDLc, high density lipoprotein cholesterol; HFW, high-fat Western-type; IDL, intermediate density lipoprotein; SR-BI, scavenger receptor class B type I; TC, total cholesterol


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