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).

Author information:
(1)From the Cardiovascular Research Laboratories, Department of Biochemistry, Faculty of Medicine, Division of Cardiology, McGill University, Royal Victoria Hospital, Montreal, Quebec, Canada (I.I., H.Y.C., I.R., Z.A., J.G.); Department of Human Genetics (M.V.P.L.R., D.W.-V., E.N., P.P.) and Department of Medicine (M.V.P.L.R., D.W.-V., E.N., P.P.), David Geffen School of Medicine at University of California at Los Angeles; Department of Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville (H.K., J.L., C.M.A.); The Lautenberg Cancer Research Center, Department of Immunology and Cancer Research, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel (M.A.O., M.A.-R., R.I.A.); The Lautenberg Center for Immunology and Cancer Research, Department of Immunology and Cancer Research-IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel and Al-Quds-Bard College for Arts and Sciences, Al-Quds University, East Jerusalem-Abu Dis, Palestine (Z.S.); and Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University, Columbus (M.C., C.M.C., R.I.A.).
(2)From the Cardiovascular Research Laboratories, Department of Biochemistry, Faculty of Medicine, Division of Cardiology, McGill University, Royal Victoria Hospital, Montreal, Quebec, Canada (I.I., H.Y.C., I.R., Z.A., J.G.); Department of Human Genetics (M.V.P.L.R., D.W.-V., E.N., P.P.) and Department of Medicine (M.V.P.L.R., D.W.-V., E.N., P.P.), David Geffen School of Medicine at University of California at Los Angeles; Department of Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville (H.K., J.L., C.M.A.); The Lautenberg Cancer Research Center, Department of Immunology and Cancer Research, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel (M.A.O., M.A.-R., R.I.A.); The Lautenberg Center for Immunology and Cancer Research, Department of Immunology and Cancer Research-IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel and Al-Quds-Bard College for Arts and Sciences, Al-Quds University, East Jerusalem-Abu Dis, Palestine (Z.S.); and Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University, Columbus (M.C., C.M.C., R.I.A.). jacques.genest@mcgill.ca.

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.

PMCID: PMC4315188

PMID: 24871327  [PubMed - indexed for MEDLINE]

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