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 III HLP, 
we have generated a variant allele at the endogenous mouse Ldlr locus that 
expresses the human LDL receptor transcript. Transcription of the human LDLR 
minigene is regulated by the endogenous mouse promoter sequence, but a 
truncation of 3'-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 III 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.