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 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.
Knouff
C
C
Curriculum in Genetics and Molecular Biology and the Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7525, USA.
Malloy
S
S
Wilder
J
J
Altenburg
M K
MK
Maeda
N
N
D020413:3' Untranslated Regions; D000818:Animals; D053329:Apolipoprotein E2; D001057:Apolipoproteins E / Q000235:genetics*; D001483:Base Sequence; D017931:DNA Primers; D006801:Humans; D006951:Hyperlipoproteinemias / Q000097:blood / Q000235:genetics*; D008055:Lipids / Q000097:blood; D051379:Mice; D008822:Mice, Transgenic; D011973:Receptors, LDL / Q000235:genetics*
D020413:3' Untranslated Regions; D053329:Apolipoprotein E2; D001057:Apolipoproteins E; D017931:DNA Primers; D008055:Lipids; D011973:Receptors, LDL