Quantitative trait locus mapping and identification of Zhx2 as a novel regulator of plasma lipid metabolism.
BACKGROUND
We previously mapped a quantitative trait locus on chromosome 15 in mice contributing to high-density lipoprotein cholesterol and triglyceride levels and now report the identification of the underlying gene.


RESULTS
We first fine-mapped the locus by studying a series of congenic strains derived from the parental strains BALB/cJ and MRL/MpJ. Analysis of gene expression and sequencing followed by transgenic complementation led to the identification of zinc fingers and homeoboxes 2 (Zhx2), a transcription factor previously implicated in the developmental regulation of alpha-fetoprotein. Reduced expression of the protein in BALB/cJ mice resulted in altered hepatic transcript levels for several genes involved in lipoprotein metabolism. Most notably, the Zhx2 mutation resulted in a failure to suppress expression of lipoprotein lipase, a gene normally silenced in the adult liver, and this was normalized in BALB/cJ mice carrying the Zhx2 transgene.


CONCLUSIONS
We identified the gene underlying the chromosome 15 quantitative trait locus, and our results show that Zhx2 functions as a novel developmental regulator of key genes influencing lipoprotein metabolism.
Gargalovic
Peter S
PS
Department of Medicine, Microbiology, University of California, Los Angeles, CA 90095-1679, USA.
Erbilgin
Ayça
A
Kohannim
Omid
O
Pagnon
Joanne
J
Wang
Xuping
X
Castellani
Lawrence
L
LeBoeuf
Renee
R
Peterson
Martha L
ML
Spear
Brett T
BT
Lusis
Aldons J
AJ
D000818:Animals; D002874:Chromosome Mapping; D005260:Female; D020869:Gene Expression Profiling; D005838:Genotype; D018398:Homeodomain Proteins / Q000235:genetics*; D050356:Lipid Metabolism / Q000235:genetics*; D008055:Lipids / Q000097:blood*; D008071:Lipoprotein Lipase / Q000235:genetics / Q000378:metabolism; D008074:Lipoproteins / Q000235:genetics; D008099:Liver / Q000201:enzymology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009154:Mutation; D040641:Quantitative Trait Loci; D012333:RNA, Messenger / Q000378:metabolism; D000509:alpha-Fetoproteins / Q000235:genetics / Q000378:metabolism
D018398:Homeodomain Proteins; C524979:Hyplip2 protein, mouse; D008055:Lipids; D008074:Lipoproteins; D012333:RNA, Messenger; C481543:Zhx2 protein, mouse; D000509:alpha-Fetoproteins; D008071:Lipoprotein Lipase