on July 10, 2008
Published online before print July 10, 2008, doi: 10.1161/ATVBAHA.108.169680
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Submitted on October 18, 2007
Accepted on June 25, 2008
Absence of Hyperlipidemia in LDL Receptor–Deficient Mice Having Apolipoprotein B100 Without the Putative Receptor-Binding Sequences
Lance A. Johnson ;
From the Department of Pathology and Laboratory Medicine (L.A.J., M.K.A., L.T.S., N.M.), The University of North Carolina at Chapel Hill; and the Poultry Science Department (R.L.W.), Texas A&M University, College Station.
* To whom correspondence should be addressed. E-mail: nobuyo{at}med.unc.edu.
Objective—To examine the effects of apoB100 structure, specifically a mutation in the LDLr binding region, on the production of LDL and development of atherosclerosis in vivo.
Methods and Results—Ldlr-/-Apobec1-/- mice lacking the LDLR and apoB editing enzyme accumulated LDL in plasma and developed severe atherosclerosis when they had wild-type apoB100. In marked contrast, in Ldlr-/-Apobec1-/- mice carrying the Apob100-
mutation, in the 2 putative LDLR-binding domains of apoB prevented both LDL accumulation and atherosclerosis. Intestinal absorption of lipids and triglyceride secretion from the liver were not affected. However, the VLDL particles with apoB100- were larger in volume by about 70%, and carried approximately four times as much apoE per particle. ApoB100- synthesis rate in the primary hepatocytes was normal, but its intracellular degradation was enhanced. Additionally, mutant apoB100 VLDL cleared from the circulation more quickly in vivo through apoE-LRP–mediated mechanism than VLDL with wild-type apoB100. In contrast, uptake of the 2 VLDL by macrophages were not different.
Conclusion—While conformational change to apoB100 during conversion of VLDL to LDL exposes LDLR binding domains and facilitates LDLR-mediated lipoprotein clearance, it may also inhibit LRP-mediated VLDL uptake and contribute to LDL accumulation in familial hypercholesterolemia.
Key words: lipoprotein clearance • atherosclerosis • apolipoprotein B100 • familial hypercholesterolemia • animal models