Quantitative Trait Locus Mapping and Identification of Zhx2 as a Novel Regulator of Plasma Lipid Metabolism

Background —We previously mapped a quantitative trait locus (QTL) on chromosome 15 in mice contributing to HDL-cholesterol and triglyceride levels and now report the identification of the underlying gene. Methods and 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 α-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 (Lpl), 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 QTL and our results show that Zhx2 functions as a novel developmental regulator of key genes influencing lipoprotein metabolism.