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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 Wu^1,2,*, Hong Yang^1,, Wei Xiang^*, LiChun Zhou^*, MingJian Shi^*, George Julies, Janice M. LaPlante, Billy R. Ballard^* and ZhongMao Guo^3,*

^* Department of Pathology, Anatomy, and Cell Biology, Meharry Medical College, Nashville, TN 37208
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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