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J. Biol. Chem., Vol. 276, Issue 6, 3856-3862, February 9, 2001

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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^*

Christopher Knouff^§, Sudi Malloy^§, Jennifer Wilder^¶, Michael K. Altenburg^¶, and Nobuyo Maeda^¶

From the  Curriculum in Genetics and Molecular Biology and the ^¶ Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7525

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.

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