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LXR-dependent regulation of macrophage-specific reverse cholesterol transport is impaired in a model of genetic diabesity

  • Author Footnotes
    1 These authors contributed equally to this work.
    Teresa L. Errico
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau – Institut d'Investigacions Biomèdiques Sant Pau (IIB-Sant Pau), Barcelona, Spain

    Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Barcelona, Spain
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Karen Alejandra Méndez-Lara
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau – Institut d'Investigacions Biomèdiques Sant Pau (IIB-Sant Pau), Barcelona, Spain

    Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Barcelona, Spain
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  • David Santos
    Affiliations
    CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Madrid, Spain
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  • Núria Cabrerizo
    Affiliations
    Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau – Institut d'Investigacions Biomèdiques Sant Pau (IIB-Sant Pau), Barcelona, Spain
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  • Lucía Baila-Rueda
    Affiliations
    CIBER de Enfermedades Cardiovasculares, Madrid, Spain

    Unidad Clínica y de Investigación en Lípidos y Arteriosclerosis, Hospital Universitario Miguel Servet, Instituto de Investigación Sanitaria Aragón (IIS Aragón), Zaragoza, Spain
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  • Jari Metso
    Affiliations
    National Institute for Health and Welfare, Genomics and Biomarkers unit, and Minerva Foundation Institute for medical Research, Biomedicum, Helsinki, Finland
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  • Ana Cenarro
    Affiliations
    CIBER de Enfermedades Cardiovasculares, Madrid, Spain

    Unidad Clínica y de Investigación en Lípidos y Arteriosclerosis, Hospital Universitario Miguel Servet, Instituto de Investigación Sanitaria Aragón (IIS Aragón), Zaragoza, Spain
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  • Eva Pardina
    Affiliations
    Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain
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  • Albert Lecube
    Affiliations
    CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Madrid, Spain

    Unitat de Recerca en Diabetes i Metabolisme, Institut de Recerca Hospital Universitari Vall d'Hebron, Barcelona, Spain
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  • Matti Jauhiainen
    Affiliations
    National Institute for Health and Welfare, Genomics and Biomarkers unit, and Minerva Foundation Institute for medical Research, Biomedicum, Helsinki, Finland
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  • Julia Peinado-Onsurbe
    Affiliations
    Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain
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  • Joan Carles Escolà-Gil
    Affiliations
    Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau – Institut d'Investigacions Biomèdiques Sant Pau (IIB-Sant Pau), Barcelona, Spain

    Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Barcelona, Spain

    CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Madrid, Spain
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  • Author Footnotes
    2 These authors are co-principal and co-corresponding authors of this work.
    Francisco Blanco-Vaca
    Correspondence
    Reprint requests: Dr Francisco Blanco-Vaca or Josep Julve, IIB-Sant Pau, C/Sant Antoni M. Claret 167, 08025 Barcelona, Spain
    Footnotes
    2 These authors are co-principal and co-corresponding authors of this work.
    Affiliations
    Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau – Institut d'Investigacions Biomèdiques Sant Pau (IIB-Sant Pau), Barcelona, Spain

    Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Barcelona, Spain

    CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Madrid, Spain
    Search for articles by this author
  • Author Footnotes
    2 These authors are co-principal and co-corresponding authors of this work.
    Josep Julve
    Correspondence
    Reprint requests: Dr Francisco Blanco-Vaca or Josep Julve, IIB-Sant Pau, C/Sant Antoni M. Claret 167, 08025 Barcelona, Spain
    Footnotes
    2 These authors are co-principal and co-corresponding authors of this work.
    Affiliations
    Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau – Institut d'Investigacions Biomèdiques Sant Pau (IIB-Sant Pau), Barcelona, Spain

    Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Barcelona, Spain

    CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Madrid, Spain
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this work.
    2 These authors are co-principal and co-corresponding authors of this work.
      Diabesity and fatty liver have been associated with low levels of high-density lipoprotein cholesterol, and thus could impair macrophage-specific reverse cholesterol transport (m-RCT). Liver X receptor (LXR) plays a critical role in m-RCT. Abcg5/g8 sterol transporters, which are involved in cholesterol trafficking into bile, as well as other LXR targets, could be compromised in the livers of obese individuals. We aimed to determine m-RCT dynamics in a mouse model of diabesity, the db/db mice. These obese mice displayed a significant retention of macrophage-derived cholesterol in the liver and reduced fecal cholesterol elimination compared with nonobese mice. This was associated with a significant downregulation of the hepatic LXR targets, including Abcg5/g8. Pharmacologic induction of LXR promoted the delivery of total tracer output into feces in db/db mice, partly due to increased liver and small intestine Abcg5/Abcg8 gene expression. Notably, a favorable upregulation of the hepatic levels of ABCG5/G8 and NR1H3 was also observed postoperatively in morbidly obese patients, suggesting a similar LXR impairment in these patients. In conclusion, our data show that downregulation of the LXR axis impairs cholesterol transfer from macrophages to feces in db/db mice, whereas the induction of the LXR axis partly restores impaired m-RCT by elevating the liver and small intestine expressions of Abcg5/g8.

      Abbreviations:

      ABC (ATP-binding cassette transporters), apo (apolipoprotein), CVD (cardiovascular disease), HDL (high-density lipoprotein), HDL-C (HDL cholesterol), LDL (low-density lipoprotein), LDL-C (LDL cholesterol), m-RCT (in vivo macrophage-specific reverse cholesterol transport), T2D (type 2 diabetes mellitus)
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