Iatan I et al. The WWOX gene modulates high-density lipoprotein and lipid metabolism. Circ Cardiovasc Genet. 2014 Aug;7(4):491-504. Epub 2014 May 28. PMID: 24871327.
Circ Cardiovasc Genet. 2014 Aug;7(4):491-504. doi: 10.1161/CIRCGENETICS.113.000248. Epub 2014 May 28.
The WWOX gene modulates high-density lipoprotein and lipid metabolism.
Iatan I(1), Choi HY(1), Ruel I(1), Reddy MV(1), Kil H(1), Lee J(1), Odeh MA(1), Salah Z(1), Abu-Remaileh M(1), Weissglas-Volkov D(1), Nikkola E(1), Civelek M(1), Awan Z(1), Croce CM(1), Aqeilan RI(1), Pajukanta P(1), Aldaz CM(1), Genest J(2).
BACKGROUND: Low levels of high-density lipoprotein (HDL) cholesterol constitutes a major risk factor for atherosclerosis. Recent studies from our group reported a genetic association between 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 WWOX in HDL and lipid metabolism.
METHODS AND RESULTS: Using next-generation resequencing of the WWOX region, 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 Wwox(hep-/-) and total Wwox(-/-) mice models, where we found decreased ApoA-I and Abca1 levels in hepatic tissues. Analyses of lipoprotein profiles in Wwox(-/-), but not Wwox(hep-/-) 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 Wwox(hep-/-) mice, where microarray analyses revealed an increase in plasma triglycerides and altered lipid metabolic pathways. We further identified a significant reduction in ApoA-I and Lpl and an upregulation in Fas, Angptl4, and Lipg, suggesting that the effects of Wwox involve multiple pathways, including cholesterol homeostasis, ApoA-I/ABCA1 pathway, and fatty acid biosynthesis/triglyceride metabolism.
CONCLUSIONS: Our data indicate that WWOX disruption alters HDL and lipoprotein metabolism through several mechanisms and may account for the low-HDL phenotype observed in families expressing the WWOX variants. These findings thus describe a novel gene involved in cellular lipid homeostasis, which effects may impact atherosclerotic disease development.
© 2014 American Heart Association, Inc.
PMID: 24871327 [PubMed - indexed for MEDLINE]