J. Lipid Res.
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Originally published In Press as doi:10.1194/jlr.M400430-JLR200 on May 1, 2005

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Journal of Lipid Research, Vol. 46, 1380-1387, July 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Heterozygous mutation of ataxia-telangiectasia mutated gene aggravates hypercholesterolemia in apoE-deficient mice

DongFang Wu1,2,*, Hong Yang1,{dagger}, Wei Xiang*, LiChun Zhou*, MingJian Shi*, George Julies{dagger}, Janice M. LaPlante§, Billy R. Ballard* and ZhongMao Guo3,*

* Department of Pathology, Anatomy, and Cell Biology, Meharry Medical College, Nashville, TN 37208
{dagger} Department of Physiology, Meharry Medical College, Nashville, TN 37208
§ Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115

Published, JLR Papers in Press, May 1, 2005. DOI 10.1194/jlr.M400430-JLR200

1 D. Wu and H. Yang contributed equally to this work.

2 Present address of D. Wu: The Renmin Hospital of Wuhan University, Wuhan City, Hubei 430060, People's Republic of China.

3 To whom correspondence should be addressed. e-mail: zguo{at}mmc.edu

Individuals with a heterozygous mutation at the ataxia-telangiectasia mutated gene (ATM) have been reported to be predisposed to ischemic heart disease. This report examined for the first time the effect of a heterozygous ATM mutation (ATM+/–) on plasma lipid levels and atherosclerosis intensity using ATM+/–, ATM+/+ (wild type), ATM+/+/LDLR–/– (low density lipoprotein receptor knockout), ATM+/–/LDLR–/–, ATM+/+/ApoE–/– (apolipoprotein E knockout), and ATM+/–/ApoE–/– mice. Our data demonstrated that the plasma cholesterol and triglyceride levels in ATM+/– and ATM+/–/LDLR–/– mice were approximately the same as those in ATM+/+ and ATM+/+/LDLR–/– control mice, respectively. In contrast, the plasma cholesterol level was significantly higher in ATM+/–/ApoE–/– mice than in ATM+/+/ApoE–/– control mice. In addition, the ATM+/–/ApoE–/– mice showed higher plasma apoB-48 levels, slower clearance for plasma apoB-48-carrying lipoproteins, and more advanced atherosclerotic lesions in the aorta compared with the ATM+/+/ApoE–/– mice.

These novel results suggest that the product of ATM is involved in an apoE-independent pathway for catabolism of apoB-48-carrying remnants; therefore, superimposition of a heterozygous ATM mutation onto an ApoE deficiency background reduces the clearance of apoB-48-carrying lipoproteins from the blood circulation and promotes the formation of atherosclerosis.

Abbreviations: apoE, apolipoprotein E; ATM, ataxia-telangiectasia mutated gene; FPLC, fast-performance liquid chromatography; LDLR, low density lipoprotein receptor; LRP, LDLR-related protein

Supplementary key words apolipoprotein E • apolipoprotein B-48-carrying lipoprotein • cholesterol • atherosclerosis


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