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

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. (Arterioscler Thromb Vasc Biol. 2008;28:1745-1752) Key Words: lipoprotein clearance atherosclerosis apolipoprotein B10