Objective: Increased expression of the low-density lipoprotein receptor (LDLR) is generally considered beneficial for reducing plasma cholesterol and atherosclerosis, and its downregulation has been thought to explain the association between apolipoprotein (apo) E4 and increased risk of coronary heart disease in humans.
Methods and results: Contrary to this hypothesis, doubling Ldlr expression caused severe atherosclerosis with marked accumulation of cholesterol-rich, apoE-poor remnants in mice with human apoE4, but not apoE3, when the animals were fed a Western-type diet. The increased Ldlr expression enhanced in vivo clearance of exogenously introduced remnants in mice with apoE4 only when the remnants were already enriched with apoE4. The rates of nascent lipoprotein production were the same. The adverse effects of increased LDLR suggest a possibility that the receptor can trap apoE4, reducing its availability for the transfer to nascent lipoproteins needed for their rapid clearance, thereby increasing the production of apoE-poor remnants that are slowly cleared. The lower affinity for the LDLR of apoE3 compared with apoE4 could then explain why increased receptor expression had no adverse effects with apoE3.
Conclusions: Our results emphasize the occurrence of important and unexpected interactions between APOE genotype, LDLR expression, and diet.