The WWOX Gene Modulates High-Density Lipoprotein and Lipid MetabolismClinical Perspective

Background— Low levels of high-density lipoprotein (HDL) cholesterol constitutes a major risk factor for atherosclerosis. Recent studies from our group reported a genetic associationbetween the WW domain-containing oxidoreductase ( WWOX) gene and HDL cholesterol levels. Here, through next-generation resequencing, in vivo functional studies and gene microarray analyses, we investigated the role of WWOXin HDL and lipid metabolism. Methods and Results— Using next-generation resequencing of the WWOXregion, we first identified 8 variants significantly associated and perfectly segregating with the low-HDL trait in 2 multigenerational French Canadian dyslipidemic families. To understand in vivo functions of WWOX, we used liver-specific Wwoxhep−/− and total Wwox−/− mice models, where we found decreased ApoA-I and Abca1levels in hepatic tissues. Analyses of lipoprotein profiles in Wwox−/−, but not Wwoxhep−/− littermates, also showed marked reductions in serum HDL cholesterol concentrations, concordant with the low-HDL findings observed in families. We next obtained evidence of a sex-specific effect in female Wwoxhep−/− mice, where microarray analyses revealed an increase in plasma triglycerides and altered lipid metabolicpathways. We further identified a significant reduction in ApoA-I and Lpl and an upregulation in Fas , Angptl4, and Lipg , suggesting that the effects of Wwoxinvolve multiple pathways, including cholesterol homeostasis, ApoA-I/ ABCA1pathway, and fatty acid biosynthesis/triglyceride metabolism. Conclusions— Our data indicate that WWOXdisruption alters HDL and lipoprotein metabolism through several mechanisms and may account for the low-HDL phenotype observed in families expressing the WWOXvariants. These findings thus describe a novel gene involved in cellular lipid homeostasis, which effects may impact atherosclerotic disease development.