| First Author | Iatan I | Year | 2014 |
| Journal | Circ Cardiovasc Genet | Volume | 7 |
| Issue | 4 | Pages | 491-504 |
| PubMed ID | 24871327 | Mgi Jnum | J:317579 |
| Mgi Id | MGI:6843498 | Doi | 10.1161/CIRCGENETICS.113.000248 |
| Citation | Iatan I, et al. (2014) The WWOX gene modulates high-density lipoprotein and lipid metabolism. Circ Cardiovasc Genet 7(4):491-504 |
| abstractText | 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. |
