出版社：American Society for Biochemistry and Molecular Biology
摘要：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.
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