The WWOX gene modulates high-density lipoprotein and lipid metabolism

Iulia 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, Jacques Genest*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

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..

Original languageAmerican English
Pages (from-to)491-504
Number of pages14
JournalCirculation: Cardiovascular Genetics
Volume7
Issue number4
DOIs
StatePublished - 1 Aug 2014

Bibliographical note

Publisher Copyright:
© 2014 American Heart Association, Inc.

Keywords

  • ABCA1
  • Apolopoprotein A-I
  • Cardiovascular diseases
  • Genetics
  • HDL Cholesterol
  • Lipids
  • WWOX protein

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