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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:1745.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Absence of Hyperlipidemia in LDL Receptor-Deficient Mice Having Apolipoprotein B100 Without the Putative Receptor-Binding Sequences

Lance A. Johnson; Michael K. Altenburg; Rosemary L. Walzem; Lori T. Scanga; Nobuyo Maeda

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.

Correspondence to Dr Nobuyo Maeda, Department of Pathology and Laboratory Medicine, The University of North Carolina at Chapel Hill, 701 Brinkhous-Bullitt Building, Chapel Hill, NC 27599-7525. 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-β 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-β were larger in volume by about 70%, and carried approximately four times as much apoE per particle. ApoB100-β 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.

Mice that lack the LDLR and ApoB editing enzyme (Ldlr^–/– Apobec1^–/–) accumulate LDL and develop severe atherosclerosis. Conversely, Ldlr^–/– Apobec1^–/– mice carrying Apob100-β with altered sequences in the putative LDLR-binding domains of apoB neither accumulate LDL nor develop atherosclerosis. This finding highlights a potential therapeutic target for patients with familial hypercholesterolemia.

Key Words: lipoprotein clearance • atherosclerosis • apolipoprotein B100 • familial hypercholesterolemia • animal models