Review Article | Published:

The role of macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis

Nature Reviews Gastroenterology & Hepatologyvolume 16pages145159 (2019) | Download Citation


Nonalcoholic fatty liver disease (NAFLD) and its inflammatory and often progressive subtype nonalcoholic steatohepatitis (NASH) are becoming the leading cause of liver-related morbidity and mortality worldwide, and a primary indication for liver transplantation. The pathophysiology of NASH is multifactorial and not yet completely understood; however, innate immunity is a major contributing factor in which liver-resident macrophages (Kupffer cells) and recruited macrophages play a central part in disease progression. In this Review, we assess the evidence for macrophage involvement in the development of steatosis, inflammation and fibrosis in NASH. In this process, not only the polarization of liver macrophages towards a pro-inflammatory phenotype is important, but adipose tissue macrophages, especially in the visceral compartment, also contribute to disease severity and insulin resistance. Macrophage activation is mediated by factors such as endotoxins and translocated bacteria owing to increased intestinal permeability, factors released from damaged or lipoapoptotic hepatocytes, as well as alterations in gut microbiota and defined nutritional components, including certain free fatty acids, cholesterol and their metabolites. Reflecting the important role of macrophages in NASH, we also review studies investigating drugs that target macrophage recruitment to the liver, macrophage polarization and their inflammatory effects as potential treatment options for patients with NASH.

Key points

  • Extensive experimental and clinical data support a central role for macrophages in the development and progression of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH).

  • Liver-resident Kupffer cells initiate inflammation and help recruit blood-derived monocytes; both differentiate into pro-inflammatory macrophages and further promote NAFLD progression.

  • Gut-derived endotoxins, lipids and lipid metabolites, and molecules associated with hepatocellular damage and death are the main factors contributing to macrophage activation in NAFLD.

  • In addition to hepatic macrophages, macrophages in adipose tissue are also associated with fatty liver disease through their effects on chronic inflammation, including cytokine and adipokine secretion.

  • Macrophage-specific biomarkers and pharmacological agents targeting macrophages show promise for the diagnosis and treatment of inflammation and fibrosis in NASH.

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The authors acknowledge the NOVO Nordisk Foundation and The Danish Strategic Research Council (grant 10–092797). J.G. is supported by the Robert W. Storr Bequest to the Sydney Medical Foundation, University of Sydney; a National Health and Medical Research Council of Australia (NHMRC) Program Grant (1053206) and Project grants 1006759 and 1047417. D.S. receives project related support from a European Research Council Advanced Grant (FIBROIMAGING), by Horizon 2020 under grant agreement no. 634413(EPoS) and 777377 (LITMUS), and by the German Research Foundation collaborative research project grants DFG CRC 1066/B3, CRC 1292/08, SPP1656-2, TR128/A08 and DFG TR156/C5.

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Author notes

  1. These authors contributed equally: Detlef Schuppan, Henning Grønbæk.


  1. Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark

    • Konstantin Kazankov
    • , Simon Mark Dahl Jørgensen
    • , Karen Louise Thomsen
    • , Hendrik Vilstrup
    •  & Henning Grønbæk
  2. Department of Internal Medicine, Randers Regional Hospital, Randers, Denmark

    • Konstantin Kazankov
  3. Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark

    • Holger Jon Møller
  4. Storr Liver Centre, The Westmead Institute for Medical Research, University of Sydney and Westmead Hospital, Westmead, New South Wales, Australia

    • Jacob George
  5. Institute of Translational Immunology and Research Center for Immunology, University Medical Center, Johannes-Gutenberg-University, Mainz, Germany

    • Detlef Schuppan
  6. Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    • Detlef Schuppan


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K.K., H.V., D.S. and H.G. were responsible for the conception of the Review. K.K. wrote the first draft of the manuscript and S.M.D.J. produced ideas for the figures. K.K., S.M.D.J., K.L.T., J.G., D.S. and H.G. researched data for the article. All authors made substantial contributions to the discussion of content.

Competing interests

H.G. received research grants from Abbvie, Intercept, Ipsen and the NOVO Nordisk Foundation, and is on the advisory board of Ipsen and Novartis. K.L.T. obtained funding from the NOVO Nordisk Foundation. The remaining authors declare no competing interests.

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Correspondence to Konstantin Kazankov.

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