Crosstalk between adipose tissue insulin resistance and liver macrophages in Non Alcoholic Fatty Liver Disease

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  • Chiara Rosso, Division of Gastroenterology and Hepatology, Department of Medical Sciences, University of Turin, Turin, Italy.
  • ,
  • Konstantin Kazankov
  • Ramy Younes, Division of Gastroenterology and Hepatology, Department of Medical Sciences, University of Turin, Turin, Italy.
  • ,
  • Saeed Esmaili, Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and the University of Sydney, Sydney, NSW, Australia.
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  • Milena Marietti, Division of Gastroenterology and Hepatology, Department of Medical Sciences, University of Turin, Turin, Italy.
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  • Marco Sacco, Division of Gastroenterology and Hepatology, Department of Medical Sciences, University of Turin, Turin, Italy.
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  • Fabrizia Carli, Cardiometabolic Risk Unit, Institute of Clinical Physiology, CNR, Pisa, Italy.
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  • Melania Gaggini, Cardiometabolic Risk Unit, Institute of Clinical Physiology, CNR, Pisa, Italy.
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  • Federico Salomone, Division of Gastroenterology, Ospedale di Acireale, Azienda Sanitaria Provinciale di Catania, Catania, Italy.
  • ,
  • Holger Jon Møller
  • Maria Lorena Abate, Division of Gastroenterology and Hepatology, Department of Medical Sciences, University of Turin, Turin, Italy.
  • ,
  • Hendrik Vilstrup
  • Amalia Gastaldelli, Cardiometabolic Risk Unit, Institute of Clinical Physiology, CNR, Pisa, Italy.
  • ,
  • Jacob George, Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and the University of Sydney, Sydney, NSW, Australia.
  • ,
  • Henning Grønbæk
  • Elisabetta Bugianesi, Division of Gastroenterology and Hepatology, Department of Medical Sciences, University of Turin, Turin, Italy. Electronic address: elisabetta.bugianesi@unito.it.

Background & Aims: The pathogenesis of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) is likely due to the interaction between a deranged metabolic milieu and local mediators of hepatic inflammation and fibrosis. We undertook this study to elucidate the interplay between macrophage activation, insulin resistance (IR) in target organs/tissues and hepatic damage. Methods: In 40 non-diabetic patients with biopsy-proven NAFLD we assessed: i) endogenous glucose production (EGP), glucose clearance and indexes of IR in the adipose tissue (Adipo-IR and Lipo-IR) and in the liver (Hep-IR) by tracer infusion ([6,6-2H2]glucose and [2H5]glycerol); ii) macrophage activity (by soluble sCD163) and iii) hepatic expression of CD163 (hCD163). Results: We found that sCD163 levels paralleled both the plasma free fatty acid (FFA) levels and lipolysis from adipose tissue. Consistently, sCD163 significantly correlated with adipose tissue IR (Adipo-IR: r = 0.32, p = 0.042; Lipo-IR: r = 0.39, p = 0.012). At multiple regression analysis, sCD163 levels were associated with FFA levels (r p = 0.35, p = 0.026). In vitro exposure of human monocyte-derived macrophages to palmitate enhanced sCD163 secretion. Conversely, sCD163 did not correlate with EGP or with Hep-IR. In the liver, hCD163 positively correlated with sCD163 (r = 0.58, p = 0.007) and the degree of steatosis (r = 0.34, p = 0.048), but not with EGP or Hep-IR (r = −0.27 and r = 0.11, respectively, p >0.10, both). Conclusions: Our findings suggest a link between deranged metabolism in the adipose tissue and activation of hepatic macrophages in patients with NAFLD, possibly in response to FFA overflow and independent of obesity and diabetes. Conversely, our findings do not support a link between activated hepatic macrophages and glucose metabolism (EGP or Hep-IR). The relationship between adipose tissue IR and hepatic macrophages should be considered to define therapeutic targets for NAFLD. Lay summary: The pathogenesis of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) is likely due to the interaction between a deranged metabolic milieu and local mediators of hepatic inflammation and fibrosis in the insulin resistant state. This study provides in vivo support for a possible link between deranged metabolism in the adipose tissue and activation of hepatic macrophages in patients with NAFLD, most likely in response to free fatty acid overflow and independent of obesity and diabetes.

Original languageEnglish
Book seriesJournal of Hepatology
Volume71
Issue5
Pages (from-to)1012-1021
Number of pages10
ISSN0169-5185
DOIs
Publication statusPublished - Nov 2019

    Research areas

  • Adipose tissue, Fibrosis, Insulin resistance, Macrophage, Steatohepatitis

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