Doubling expression of the low density lipoprotein receptor by truncation of the 3′-untranslated region sequence ameliorates type III hyperlipoproteinemia in mice expressing the human ApoE2 isoform

The primary receptor mediating clearance of apolipoprotein (apo)E- and apoB100-containing lipoproteins from the circulation is the low density lipoprotein (LDL) receptor, Reduced expression of the LDLR is believed to be a precipitating factor in the pathogenesis of type III hyperlipoproteinemia (HLP) in some humans homozygous for the apoE2 allele (APOE*2). To test the effect of genetic changes in LDL receptor expression on the pathogenesis of type Ill HLP, we have generated a variant allele at the endogenous mouse Ldlr locus that ex presses the human LDL receptor transcript. Transcription of the human LDLR minigene is regulated by the endogenous mouse promoter sequence, but a truncation of S'-untranslated region results in increased mRNA stability. Consequently, in liver of heterozygotes, steady state levels of mouse and human LDLR transcripts are 50 and 180% the levels of total transcript in wild type mice, respectively. Overall, the 2.3-fold normal level of LDLR message in heterozygotes completely ameliorates type II HLP caused by the homozygosity for the human APOE*2 allele, normalizing their plasma lipoprotein profile. We conclude that a modest increase in expression of the LDLR through message stabilization is sufficient to prevent precipitation of type III HLP in mice.