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Circulating levels and hepatic expression of molecular mediators of atherosclerosis in nonalcoholic fatty liver disease

  • Silvia Sookoian
    Correspondence
    Corresponding authors at: Instituto de Investigaciones Médicas, UBA-CONICET, Combatiente de Malvinas 3150, Buenos Aires 1427, Argentina. Tel.: +54 11 4514 8701x167; fax: +54 11 4523 8947.
    Affiliations
    Laboratory of Clinical and Molecular Hepatology, Molecular Genetics and Biology of Complex Diseases Department, Institute of Medical Research A Lanari-IDIM, University of Buenos Aires-National Council of Scientific and Technological Research (CONICET), Ciudad Autónoma de Buenos Aires, Argentina

    Research Council of GCBA, Ciudad Autónoma de Buenos Aires, Argentina

    Medicine and Surgery Department, Hospital Abel Zubizarreta, Ciudad Autónoma de Buenos Aires, Argentina
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  • Gustavo O. Castaño
    Affiliations
    Research Council of GCBA, Ciudad Autónoma de Buenos Aires, Argentina

    Medicine and Surgery Department, Hospital Abel Zubizarreta, Ciudad Autónoma de Buenos Aires, Argentina
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  • Adriana L. Burgueño
    Affiliations
    Laboratory of Molecular Genetics and Biology of the Metabolic Syndrome, Molecular Genetics and Biology of Complex Diseases Department, Institute of Medical Research A Lanari-IDIM, University of Buenos Aires-National Council of Scientific and Technological Research (CONICET), Ciudad Autónoma de Buenos Aires, Argentina
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  • María Soledad Rosselli
    Affiliations
    Laboratory of Clinical and Molecular Hepatology, Molecular Genetics and Biology of Complex Diseases Department, Institute of Medical Research A Lanari-IDIM, University of Buenos Aires-National Council of Scientific and Technological Research (CONICET), Ciudad Autónoma de Buenos Aires, Argentina

    Laboratory of Molecular Genetics and Biology of the Metabolic Syndrome, Molecular Genetics and Biology of Complex Diseases Department, Institute of Medical Research A Lanari-IDIM, University of Buenos Aires-National Council of Scientific and Technological Research (CONICET), Ciudad Autónoma de Buenos Aires, Argentina
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  • Tomas Fernández Gianotti
    Affiliations
    Laboratory of Molecular Genetics and Biology of the Metabolic Syndrome, Molecular Genetics and Biology of Complex Diseases Department, Institute of Medical Research A Lanari-IDIM, University of Buenos Aires-National Council of Scientific and Technological Research (CONICET), Ciudad Autónoma de Buenos Aires, Argentina
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  • Pablo Mallardi
    Affiliations
    Pathology Department, Hospital Diego Thompson, San Martin, Buenos Aires, Argentina
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  • Julio San Martino
    Affiliations
    Pathology Department, Hospital Diego Thompson, San Martin, Buenos Aires, Argentina
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  • Carlos Jose Pirola
    Correspondence
    Corresponding authors at: Instituto de Investigaciones Médicas, UBA-CONICET, Combatiente de Malvinas 3150, Buenos Aires 1427, Argentina. Tel.: +54 11 4514 8701x167; fax: +54 11 4523 8947.
    Affiliations
    Laboratory of Molecular Genetics and Biology of the Metabolic Syndrome, Molecular Genetics and Biology of Complex Diseases Department, Institute of Medical Research A Lanari-IDIM, University of Buenos Aires-National Council of Scientific and Technological Research (CONICET), Ciudad Autónoma de Buenos Aires, Argentina
    Search for articles by this author

      Abstract

      Objectives

      We evaluated circulating levels of biomarkers of atherosclerosis (soluble intercellular adhesion molecule: sICAM-1, plasminogen activator inhibitor: PAI-1 and soluble CD40 ligand: sCD40L) in patients with NAFLD proven through biopsy and control subjects, and correlated them with the histological disease severity. We further explored liver protein expression of ICAM-1, CD40 and PAI-1 in patients with different histological forms of NAFLD and control liver biopsies.

      Patients and methods

      We included 215 individuals: 113 patients with NAFLD (simple steatosis n = 45 and NASH n = 68) and 102 control subjects. Circulating levels of the biomarkers were measured by ELISA. Liver expression of ICAM-1, CD40 and PAI-1 was assessed by immunohistochemistry using monoclonal antihuman antibodies.

      Results

      Patients with NAFLD, in comparison with control subjects, showed significantly higher circulating levels of sICAM-1 (605.3 ± 34.6 ng/ml vs. 356.5 ± 24.6 ng/ml, p = 5.9 × 10−6), PAI-1 (22.8 ± 1.7 ng/ml vs. 19.0 ± 2.1 ng/ml, p = 0.0149) and sCD40L (1347.5 ± 513.7 pg/ml vs. 804.5 ± 396.1 pg/ml, p = 0.0229), results expressed as mean ± SE. sICAM-1 was a strong predictor of histological severity of NAFLD, after adjusting for potential confounders. In addition, patients with NAFLD showed significantly higher liver staining scores for ICAM-1 and PAI-1 than control liver biopsies. ICAM-1 immunoreactivity in lobular inflammatory infiltrate showed high scores in NASH patients; a significant correlation was found between both the degree of liver steatosis and the severity of necroinflammatory activity and liver ICAM-1 expression.

      Conclusions

      Our study shows that NAFLD is associated with elevated circulating levels and abnormal liver expression of molecular mediators of atherosclerosis. Additionally, ICAM-1 may be involved in liver damage and inflammation.

      Abbreviations:

      NAFLD (nonalcoholic fatty liver disease), NASH (nonalcoholic steatohepatitis), PAI-1 (plasminogen activator inhibitor-1), sICAM-1 (soluble intercellular adhesion molecule-1), sCD40L (soluble CD40 ligand), ELISA (enzyme-linked immuno-sorbent assay)

      Keywords

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