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

Abstract
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 Wwoxhep−/− 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 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 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.
- Received July 3, 2013.
- Accepted April 23, 2014.
- © 2014 American Heart Association, Inc.
This Issue
Jump to
Article Tools
- The WWOX Gene Modulates High-Density Lipoprotein and Lipid MetabolismClinical PerspectiveIulia Iatan, Hong Y. Choi, Isabelle Ruel, M.V. Prasad Linga Reddy, Hyunsuk Kil, Jaeho Lee, Mohammad Abu Odeh, Zaidoun Salah, Muhannad Abu-Remaileh, Daphna Weissglas-Volkov, Elina Nikkola, Mete Civelek, Zuhier Awan, Carlo M. Croce, Rami I. Aqeilan, Päivi Pajukanta, C. Marcelo Aldaz and Jacques GenestCirculation: Genomic and Precision Medicine. 2014;7:491-504, originally published May 28, 2014https://doi.org/10.1161/CIRCGENETICS.113.000248
Citation Manager Formats
Share this Article
- The WWOX Gene Modulates High-Density Lipoprotein and Lipid MetabolismClinical PerspectiveIulia Iatan, Hong Y. Choi, Isabelle Ruel, M.V. Prasad Linga Reddy, Hyunsuk Kil, Jaeho Lee, Mohammad Abu Odeh, Zaidoun Salah, Muhannad Abu-Remaileh, Daphna Weissglas-Volkov, Elina Nikkola, Mete Civelek, Zuhier Awan, Carlo M. Croce, Rami I. Aqeilan, Päivi Pajukanta, C. Marcelo Aldaz and Jacques GenestCirculation: Genomic and Precision Medicine. 2014;7:491-504, originally published May 28, 2014https://doi.org/10.1161/CIRCGENETICS.113.000248