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

DongFang Wu, Hong Yang, Wei Xiang, LiChun Zhou, MingJian Shi, George Julies, Janice M. LaPlante, Billy R. Ballard, and ZhongMao Guo

Pathology, Anatomy & Cell Biology, Meharry Medical College, Nashiville, TN 37208

Corresponding Author: 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 apolipoprotein B48 levels, slower clearance for plasma apolipoprotein B48-carrying lipoproteins and more advanced atherosclerotic lesions in the aorta when compared to the ATM+/+/ApoE-/- mice. These novel results suggest that the product of ATM is involved in an ApoE-independent pathway for catabolism of apolipoprotein B48-carrying remnants, and therefore superimposition of a heterozygous ATM mutation onto an ApoE deficiency background reduces the clearance of apolipoprotein B48-carrying lipoproteins from the blood circulation, and promotes the formation of atherosclerosis.

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