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

Abstract

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 knock-out), 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. Copyright © 2005 by the American Society for Biochemistry and Molecular Biology, Inc.