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The WWOX gene modulates high-density lipoprotein and lipid metabolism.
Iatan, Iulia; Choi, Hong Y; Ruel, Isabelle; Reddy, M V Prasad Linga; Kil, Hyunsuk; Lee, Jaeho; Odeh, Mohammad Abu; Salah, Zaidoun; Abu-Remaileh, Muhannad; Weissglas-Volkov, Daphna; Nikkola, Elina; Civelek, Mete; Awan, Zuhier; Croce, Carlo M; Aqeilan, Rami I; Pajukanta, Päivi; Aldaz, C Marcelo; Genest, Jacques.
Afiliación
  • Iatan I; 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
  • Choi HY; 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
  • Ruel I; 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
  • Reddy MV; 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
  • Kil H; 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
  • Lee J; 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
  • Odeh MA; 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
  • Salah Z; 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
  • Abu-Remaileh M; 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
  • Weissglas-Volkov D; 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
  • Nikkola E; 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
  • Civelek M; 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
  • Awan Z; 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
  • Croce CM; 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
  • Aqeilan RI; 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
  • Pajukanta P; 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
  • Aldaz CM; 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
  • Genest J; 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
Circ Cardiovasc Genet ; 7(4): 491-504, 2014 Aug.
Article en En | MEDLINE | ID: mdl-24871327
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 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.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Oxidorreductasas / Proteínas Supresoras de Tumor / Metabolismo de los Lípidos / Lipoproteínas HDL Tipo de estudio: Prognostic_studies / Risk_factors_studies Idioma: En Revista: Circ Cardiovasc Genet Asunto de la revista: ANGIOLOGIA / CARDIOLOGIA / GENETICA MEDICA Año: 2014 Tipo del documento: Article
Texto completo
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XML
PubMed Links
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Oxidorreductasas / Proteínas Supresoras de Tumor / Metabolismo de los Lípidos / Lipoproteínas HDL Tipo de estudio: Prognostic_studies / Risk_factors_studies Idioma: En Revista: Circ Cardiovasc Genet Asunto de la revista: ANGIOLOGIA / CARDIOLOGIA / GENETICA MEDICA Año: 2014 Tipo del documento: Article