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  • Review Article
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The role of macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis

Abstract

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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Fig. 1: Macrophage polarization and phenotype in liver inflammation and fibrosis.
Fig. 2: Factors contributing to macrophage activation and the principle effector pathways in NAFLD and NASH.
Fig. 3: Treatment options and their targets on macrophages for NAFLD and NASH.

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References

  1. Vernon, G., Baranova, A. & Younossi, Z. M. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment. Pharmacol. Ther. 34, 274–285 (2011).

    CAS  PubMed  Google Scholar 

  2. Wong, R. J. et al. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology 148, 547–555 (2015).

    PubMed  Google Scholar 

  3. Angulo, P. et al. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology 149, 389–397 (2015).

    PubMed  Google Scholar 

  4. Schuppan, D., Surabattula, R. & Wang, X. Y. Determinants of fibrosis progression and regression in NASH. J. Hepatol. 68, 238–250 (2018). This comprehensive review provides an insight into the epidemiology, key mechanisms, diagnostic tools and treatment options for liver fibrosis in NAFLD.

    CAS  PubMed  Google Scholar 

  5. Tilg, H. & Moschen, A. R. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology 52, 1836–1846 (2010).

    CAS  PubMed  Google Scholar 

  6. Maher, J. J., Leon, P. & Ryan, J. C. Beyond insulin resistance: innate immunity in nonalcoholic steatohepatitis. Hepatology 48, 670–678 (2008).

    CAS  PubMed  Google Scholar 

  7. Kolios, G., Valatas, V. & Kouroumalis, E. Role of Kupffer cells in the pathogenesis of liver disease. World J. Gastroenterol. 12, 7413–7420 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Gomez Perdiguero, E. et al. Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature 518, 547–551 (2015).

    PubMed  Google Scholar 

  9. Krenkel, O. & Tacke, F. Liver macrophages in tissue homeostasis and disease. Nat. Rev. Immunol. 17, 306–321 (2017).

    CAS  PubMed  Google Scholar 

  10. Mass, E. et al. Specification of tissue-resident macrophages during organogenesis. Science 353, aaf4238 (2016).

    PubMed  PubMed Central  Google Scholar 

  11. Scott, C. L. et al. Bone marrow-derived monocytes give rise to self-renewing and fully differentiated Kupffer cells. Nat. Commun. 7, 10321 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Heymann, F. & Tacke, F. Immunology in the liver — from homeostasis to disease. Nat. Rev. Gastroenterol. Hepatol. 13, 88–110 (2016).

    CAS  PubMed  Google Scholar 

  13. Tacke, F. Targeting hepatic macrophages to treat liver diseases. J. Hepatol. 66, 1300–1312 (2017).

    CAS  PubMed  Google Scholar 

  14. Heymann, F. et al. Liver inflammation abrogates immunological tolerance induced by Kupffer cells. Hepatology 62, 279–291 (2015).

    CAS  PubMed  Google Scholar 

  15. Tacke, F. & Zimmermann, H. W. Macrophage heterogeneity in liver injury and fibrosis. J. Hepatol. 60, 1090–1096 (2014).

    CAS  PubMed  Google Scholar 

  16. Karlmark, K. R. et al. Hepatic recruitment of the inflammatory Gr1+ monocyte subset upon liver injury promotes hepatic fibrosis. Hepatology 50, 261–274 (2009).

    CAS  PubMed  Google Scholar 

  17. Mehal, W. Z. & Schuppan, D. Antifibrotic therapies in the liver. Semin. Liver Dis. 35, 184–198 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Pellicoro, A., Ramachandran, P., Iredale, J. P. & Fallowfield, J. A. Liver fibrosis and repair: immune regulation of wound healing in a solid organ. Nat. Rev. Immunol. 14, 181–194 (2014).

    CAS  PubMed  Google Scholar 

  19. Ramachandran, P. et al. Differential Ly-6C expression identifies the recruited macrophage phenotype, which orchestrates the regression of murine liver fibrosis. Proc. Natl Acad. Sci. USA 109, E3186–E3195 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Duffield, J. S. et al. Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J. Clin. Invest. 115, 56–65 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Eming, S. A., Wynn, T. A. & Martin, P. Inflammation and metabolism in tissue repair and regeneration. Science 356, 1026–1030 (2017).

    CAS  PubMed  Google Scholar 

  22. Murray, P. J. et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 41, 14–20 (2014). This consensus paper provides an important overview of macrophages in terms of their origin, factors contributing to macrophage activation and the markers to describe different macrophage phenotypes.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Popov, Y. et al. Macrophage-mediated phagocytosis of apoptotic cholangiocytes contributes to reversal of experimental biliary fibrosis. Am. J. Physiol. Gastrointest. Liver Physiol. 298, G323–G334 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Schuppan, D. & Kim, Y. O. Evolving therapies for liver fibrosis. J. Clin. Invest. 123, 1887–1901 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Wang, X. et al. Gliptins suppress inflammatory macrophage activation to mitigate inflammation, fibrosis, oxidative stress, and vascular dysfunction in models of nonalcoholic steatohepatitis and liver fibrosis. Antioxid. Redox Signal. 28, 87–109 (2018).

    CAS  PubMed  Google Scholar 

  26. Weng, S. Y. et al. IL-4 receptor α signaling through macrophages differentially regulates liver fibrosis progression and reversal. EBioMedicine 29, 92–103 (2018).

    PubMed  PubMed Central  Google Scholar 

  27. Ding, T. et al. High tumor-infiltrating macrophage density predicts poor prognosis in patients with primary hepatocellular carcinoma after resection. Hum. Pathol. 40, 381–389 (2009).

    CAS  PubMed  Google Scholar 

  28. Kuang, D. M. et al. Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1. J. Exp. Med. 206, 1327–1337 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Wan, S. et al. Tumor-associated macrophages produce interleukin 6 and signal via STAT3 to promote expansion of human hepatocellular carcinoma stem cells. Gastroenterology 147, 1393–1404 (2014).

    CAS  PubMed  Google Scholar 

  30. Kazankov, K. et al. Macrophage activation marker soluble CD163 may predict disease progression in hepatocellular carcinoma. Scand. J. Clin. Lab. Invest. 76, 64–73 (2016).

    CAS  PubMed  Google Scholar 

  31. Waidmann, O. et al. Diagnostic and prognostic significance of cell death and macrophage activation markers in patients with hepatocellular carcinoma. J. Hepatol. 59, 769–779 (2013).

    CAS  PubMed  Google Scholar 

  32. Li, X. et al. Targeting of tumour-infiltrating macrophages via CCL2/CCR2 signalling as a therapeutic strategy against hepatocellular carcinoma. Gut 66, 157–167 (2017).

    CAS  PubMed  Google Scholar 

  33. Park, J. W., Jeong, G., Kim, S. J., Kim, M. K. & Park, S. M. Predictors reflecting the pathological severity of non-alcoholic fatty liver disease: comprehensive study of clinical and immunohistochemical findings in younger Asian patients. J. Gastroenterol. Hepatol. 22, 491–497 (2007).

    CAS  PubMed  Google Scholar 

  34. Lotowska, J. M., Sobaniec-Lotowska, M. E. & Lebensztejn, D. M. The role of Kupffer cells in the morphogenesis of nonalcoholic steatohepatitis — ultrastructural findings. The first report in pediatric patients. Scand. J. Gastroenterol. 48, 352–357 (2013).

    CAS  PubMed  Google Scholar 

  35. Gadd, V. L. et al. The portal inflammatory infiltrate and ductular reaction in human nonalcoholic fatty liver disease. Hepatology 59, 1393–1405 (2014). This clinical study emphasizes the role of macrophages in NAFLD, demonstrating that portal macrophage infiltration is an early event in the development of NASH and is associated with progressive disease.

    PubMed  Google Scholar 

  36. Itoh, M. et al. Hepatic crown-like structure: a unique histological feature in non-alcoholic steatohepatitis in mice and humans. PLOS ONE 8, e82163 (2013).

    PubMed  PubMed Central  Google Scholar 

  37. Rensen, S. S. et al. Increased hepatic myeloperoxidase activity in obese subjects with nonalcoholic steatohepatitis. Am. J. Pathol. 175, 1473–1482 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Ioannou, G. N., Haigh, W. G., Thorning, D. & Savard, C. Hepatic cholesterol crystals and crown-like structures distinguish NASH from simple steatosis. J. Lipid Res. 54, 1326–1334 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Kiki, I. et al. Effect of high fat diet on the volume of liver and quantitative feature of Kupffer cells in the female rat: a stereological and ultrastructural study. Obes. Surg. 17, 1381–1388 (2007).

    PubMed  Google Scholar 

  40. Lanthier, N. et al. Kupffer cell activation is a causal factor for hepatic insulin resistance. Am. J. Physiol. Gastrointest. Liver Physiol. 298, G107–G116 (2010).

    CAS  PubMed  Google Scholar 

  41. Tosello-Trampont, A. C., Landes, S. G., Nguyen, V., Novobrantseva, T. I. & Hahn, Y. S. Kuppfer cells trigger nonalcoholic steatohepatitis development in diet-induced mouse model through tumor necrosis factor-α production. J. Biol. Chem. 287, 40161–40172 (2012). This experimental study demonstrates that Kupffer cells producing TNF are instrumental in the early phases of steatohepatitis by initiating inflammation and promoting monocyte recruitment.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Fontana, L. et al. Aging promotes the development of diet-induced murine steatohepatitis but not steatosis. Hepatology 57, 995–1004 (2013).

    CAS  PubMed  Google Scholar 

  43. de Meijer, V. E., Sverdlov, D. Y., Le, H. D., Popov, Y. & Puder, M. Tissue-specific differences in inflammatory infiltrate and matrix metalloproteinase expression in adipose tissue and liver of mice with diet-induced obesity. Hepatol. Res. 42, 601–610 (2012).

    PubMed  Google Scholar 

  44. Clementi, A. H., Gaudy, A. M., van, R. N., Pierce, R. H. & Mooney, R. A. Loss of Kupffer cells in diet-induced obesity is associated with increased hepatic steatosis, STAT3 signaling, and further decreases in insulin signaling. Biochim. Biophys. Acta 1792, 1062–1072 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Ni, Y. et al. Astaxanthin prevents and reverses diet-induced insulin resistance and steatohepatitis in mice: a comparison with vitamin E. Sci. Rep. 5, 17192 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Larter, C. Z. & Yeh, M. M. Animal models of NASH: getting both pathology and metabolic context right. J. Gastroenterol. Hepatol. 23, 1635–1648 (2008).

    PubMed  Google Scholar 

  47. Lau, J. K., Zhang, X. & Yu, J. Animal models of non-alcoholic fatty liver disease: current perspectives and recent advances. J. Pathol. 241, 36–44 (2017).

    PubMed  Google Scholar 

  48. Van Herck, M. A., Vonghia, L. & Francque, S. M. Animal models of nonalcoholic fatty liver disease — a starter’s guide. Nutrients 9, 1072 (2017).

    PubMed Central  Google Scholar 

  49. Huang, W. et al. Depletion of liver Kupffer cells prevents the development of diet-induced hepatic steatosis and insulin resistance. Diabetes 59, 347–357 (2010).

    CAS  PubMed  Google Scholar 

  50. Neyrinck, A. M. et al. Critical role of Kupffer cells in the management of diet-induced diabetes and obesity. Biochem. Biophys. Res. Commun. 385, 351–356 (2009).

    CAS  PubMed  Google Scholar 

  51. Stienstra, R. et al. Kupffer cells promote hepatic steatosis via interleukin-1β-dependent suppression of peroxisome proliferator-activated receptor α activity. Hepatology 51, 511–522 (2010). This study using a mouse model of NAFLD highlights the role of Kupffer cells in the development of hepatic steatosis via secretion of IL-1β.

    CAS  PubMed  Google Scholar 

  52. Stienstra, R. et al. Peroxisome proliferator-activated receptor α protects against obesity-induced hepatic inflammation. Endocrinology 148, 2753–2763 (2007).

    CAS  PubMed  Google Scholar 

  53. Miura, K., Yang, L., van, R. N., Ohnishi, H. & Seki, E. Hepatic recruitment of macrophages promotes nonalcoholic steatohepatitis through CCR2. Am. J. Physiol. Gastrointest. Liver Physiol. 302, G1310–G1321 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Rivera, C. A. et al. Toll-like receptor-4 signaling and Kupffer cells play pivotal roles in the pathogenesis of non-alcoholic steatohepatitis. J. Hepatol. 47, 571–579 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Mills, C. D., Kincaid, K., Alt, J. M., Heilman, M. J. & Hill, A. M. M-1/M-2 macrophages and the Th1/Th2 paradigm. J. Immunol. 164, 6166–6173 (2000).

    CAS  PubMed  Google Scholar 

  56. Maina, V. et al. Bias in macrophage activation pattern influences non-alcoholic steatohepatitis (NASH) in mice. Clin. Sci. 122, 545–553 (2012).

    CAS  Google Scholar 

  57. Wan, J. et al. M2 Kupffer cells promote M1 Kupffer cell apoptosis: a protective mechanism against alcoholic and nonalcoholic fatty liver disease. Hepatology 59, 130–142 (2014). This study suggests that the anti-inflammatory macrophage phenotype might be beneficial in NAFLD.

    CAS  PubMed  Google Scholar 

  58. Papackova, Z. et al. Kupffer cells ameliorate hepatic insulin resistance induced by high-fat diet rich in monounsaturated fatty acids: the evidence for the involvement of alternatively activated macrophages. Nutr. Metab. 9, 22 (2012).

    CAS  Google Scholar 

  59. Odegaard, J. I. et al. Alternative M2 activation of Kupffer cells by PPARδ ameliorates obesity-induced insulin resistance. Cell Metab. 7, 496–507 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Jindal, A. et al. Fat-laden macrophages modulate lobular inflammation in nonalcoholic steatohepatitis (NASH). Exp. Mol. Pathol. 99, 155–162 (2015).

    CAS  PubMed  Google Scholar 

  61. Hart, K. M. et al. Type 2 immunity is protective in metabolic disease but exacerbates NAFLD collaboratively with TGF-β. Sci. Transl Med. 9, eaal3694 (2017).

    PubMed  Google Scholar 

  62. Svendsen, P. et al. Antibody-directed glucocorticoid targeting to CD163 in M2-type macrophages attenuates fructose-induced liver inflammatory changes. Mol. Ther. Methods Clin. Dev. 4, 50–61 (2017). This study demonstrates that direct targeting of macrophages by a conjugated glucocorticoid improves liver histology in a fructose-induced rat model of NASH, suggesting this approach as a potential treatment for steatohepatitis.

    CAS  PubMed  Google Scholar 

  63. Deshmane, S. L., Kremlev, S., Amini, S. & Sawaya, B. E. Monocyte chemoattractant protein-1 (MCP-1): an overview. J. Interferon Cytokine Res. 29, 313–326 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Obstfeld, A. E. et al. C-C chemokine receptor 2 (CCR2) regulates the hepatic recruitment of myeloid cells that promote obesity-induced hepatic steatosis. Diabetes 59, 916–925 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Morinaga, H. et al. Characterization of distinct subpopulations of hepatic macrophages in HFD/obese mice. Diabetes 64, 1120–1130 (2015). This mouse study highlights that Kupffer cells and monocyte-derived macrophages in NAFLD are morphologically different, comprising two distinct subpopulations of hepatic macrophages.

    CAS  PubMed  Google Scholar 

  66. Krenkel, O. et al. Therapeutic inhibition of inflammatory monocyte recruitment reduces steatohepatitis and liver fibrosis. Hepatology 67, 1270–1283 (2018).

    CAS  PubMed  Google Scholar 

  67. Deng, Z. B. et al. Immature myeloid cells induced by a high-fat diet contribute to liver inflammation. Hepatology 50, 1412–1420 (2009).

    CAS  PubMed  Google Scholar 

  68. Yang, S. J., IglayReger, H. B., Kadouh, H. C. & Bodary, P. F. Inhibition of the chemokine (C-C motif) ligand 2/chemokine (C-C motif) receptor 2 pathway attenuates hyperglycaemia and inflammation in a mouse model of hepatic steatosis and lipoatrophy. Diabetologia 52, 972–981 (2009).

    CAS  PubMed  Google Scholar 

  69. Weisberg, S. P. et al. CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J. Clin. Invest. 116, 115–124 (2006). This study demonstrates that inhibition of CCR2 improves insulin sensitivity and hepatic steatosis, highlighting the distinctive role of monocyte-derived macrophages in obesity and NAFLD.

    CAS  PubMed  Google Scholar 

  70. Baeck, C. et al. Pharmacological inhibition of the chemokine CCL2 (MCP-1) diminishes liver macrophage infiltration and steatohepatitis in chronic hepatic injury. Gut 61, 416–426 (2012).

    CAS  PubMed  Google Scholar 

  71. Frasinariu, O. E., Ceccarelli, S., Alisi, A., Moraru, E. & Nobili, V. Gut-liver axis and fibrosis in nonalcoholic fatty liver disease: an input for novel therapies. Dig. Liver Dis. 45, 543–551 (2013).

    CAS  PubMed  Google Scholar 

  72. Budick-Harmelin, N. et al. Triglycerides potentiate the inflammatory response in rat Kupffer cells. Antioxid. Redox Signal. 10, 2009–2022 (2008).

    CAS  PubMed  Google Scholar 

  73. Kawaratani, H. et al. Innate immune reactivity of the liver in rats fed a choline-deficient L-amino-acid-defined diet. World J. Gastroenterol. 14, 6655–6661 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Leroux, A. et al. Toxic lipids stored by Kupffer cells correlates with their pro-inflammatory phenotype at an early stage of steatohepatitis. J. Hepatol. 57, 141–149 (2012). This mouse study demonstrates that Kupffer cells contain lipid droplets and that these lipid-laden Kupffer cells are prone to pro-inflammatory activation, providing a link between lipotoxicity and macrophage activation.

    CAS  PubMed  Google Scholar 

  75. Kudo, H. et al. Lipopolysaccharide triggered TNF-α-induced hepatocyte apoptosis in a murine non-alcoholic steatohepatitis model. J. Hepatol. 51, 168–175 (2009).

    CAS  PubMed  Google Scholar 

  76. Ye, D. et al. Toll-like receptor-4 mediates obesity-induced non-alcoholic steatohepatitis through activation of X-box binding protein-1 in mice. Gut 61, 1058–1067 (2012).

    CAS  PubMed  Google Scholar 

  77. Vespasiani-Gentilucci, U. et al. Hepatic toll-like receptor 4 expression is associated with portal inflammation and fibrosis in patients with NAFLD. Liver Int. 35, 569–581 (2015).

    CAS  PubMed  Google Scholar 

  78. Spruss, A. et al. Toll-like receptor 4 is involved in the development of fructose-induced hepatic steatosis in mice. Hepatology 50, 1094–1104 (2009).

    CAS  PubMed  Google Scholar 

  79. Wagnerberger, S. et al. Toll-like receptors 1–9 are elevated in livers with fructose-induced hepatic steatosis. Br. J. Nutr. 107, 1727–1738 (2012).

    CAS  PubMed  Google Scholar 

  80. Miura, K. et al. Toll-like receptor 9 promotes steatohepatitis by induction of interleukin-1β in mice. Gastroenterology 139, 323–334 (2010).

    CAS  PubMed  Google Scholar 

  81. Li, L. et al. Nuclear factor high-mobility group box 1 mediating the activation of Toll-like receptor 4 signaling in hepatocytes in the early stage of nonalcoholic fatty liver disease in mice. Hepatology 54, 1620–1630 (2011).

    CAS  PubMed  Google Scholar 

  82. Jia, L. et al. Hepatocyte Toll-like receptor 4 regulates obesity-induced inflammation and insulin resistance. Nat. Commun. 5, 3878 (2014).

    CAS  PubMed  Google Scholar 

  83. Neuschwander-Tetri, B. A. Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: the central role of nontriglyceride fatty acid metabolites. Hepatology 52, 774–788 (2010).

    PubMed  Google Scholar 

  84. Lee, J. Y., Sohn, K. H., Rhee, S. H. & Hwang, D. Saturated fatty acids, but not unsaturated fatty acids, induce the expression of cyclooxygenase-2 mediated through Toll-like receptor 4. J. Biol. Chem. 276, 16683–16689 (2001).

    CAS  PubMed  Google Scholar 

  85. Lee, J. Y. et al. Reciprocal modulation of Toll-like receptor-4 signaling pathways involving MyD88 and phosphatidylinositol 3-kinase/AKT by saturated and polyunsaturated fatty acids. J. Biol. Chem. 278, 37041–37051 (2003).

    CAS  PubMed  Google Scholar 

  86. Snodgrass, R. G., Huang, S., Choi, I. W., Rutledge, J. C. & Hwang, D. H. Inflammasome-mediated secretion of IL-1β in human monocytes through TLR2 activation; modulation by dietary fatty acids. J. Immunol. 191, 4337–4347 (2013).

    CAS  PubMed  Google Scholar 

  87. Miura, K. et al. Toll-like receptor 2 and palmitic acid cooperatively contribute to the development of nonalcoholic steatohepatitis through inflammasome activation in mice. Hepatology 57, 577–589 (2013). This study demonstrates cooperative activation of Kupffer cells by palmitate and TLR2, supporting the mechanism of macrophage activation by FFAs.

    CAS  PubMed  Google Scholar 

  88. Kim, S. Y. et al. Pro-inflammatory hepatic macrophages generate ROS through NADPH oxidase 2 via endocytosis of monomeric TLR4-MD2 complex. Nat. Commun. 8, 2247 (2017).

    PubMed  PubMed Central  Google Scholar 

  89. Pal, D. et al. Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance. Nat. Med. 18, 1279–1285 (2012).

    CAS  PubMed  Google Scholar 

  90. Bohm, T. et al. Food-derived peroxidized fatty acids may trigger hepatic inflammation: a novel hypothesis to explain steatohepatitis. J. Hepatol. 59, 563–570 (2013).

    CAS  PubMed  Google Scholar 

  91. Obara, N. et al. Possible involvement and the mechanisms of excess trans-fatty acid consumption in severe NAFLD in mice. J. Hepatol. 53, 326–334 (2010).

    CAS  PubMed  Google Scholar 

  92. Musso, G., Gambino, R. & Cassader, M. Cholesterol metabolism and the pathogenesis of non-alcoholic steatohepatitis. Prog. Lipid Res. 52, 175–191 (2013).

    CAS  PubMed  Google Scholar 

  93. Ioannou, G. N. et al. Cholesterol crystallization within hepatocyte lipid droplets and its role in murine NASH. J. Lipid Res. 58, 1067–1079 (2017). This study demonstrates that Kupffer cells process cholesterol crystals, which lead to Kupffer cell activation in association with the development of NASH, highlighting macrophage activation by cholesterol.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Kunjathoor, V. V. et al. Scavenger receptors class A-I/II and CD36 are the principal receptors responsible for the uptake of modified low density lipoprotein leading to lipid loading in macrophages. J. Biol. Chem. 277, 49982–49988 (2002).

    CAS  PubMed  Google Scholar 

  95. Bieghs, V. et al. Trapping of oxidized LDL in lysosomes of Kupffer cells is a trigger for hepatic inflammation. Liver Int. 33, 1056–1061 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Bieghs, V. et al. Role of scavenger receptor A and CD36 in diet-induced nonalcoholic steatohepatitis in hyperlipidemic mice. Gastroenterology 138, 2477–2486, 2486 (2010).

    CAS  PubMed  Google Scholar 

  97. Bieghs, V. et al. Internalization of modified lipids by CD36 and SR-A leads to hepatic inflammation and lysosomal cholesterol storage in Kupffer cells. PLOS ONE 7, e34378 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Bieghs, V. et al. Specific immunization strategies against oxidized low-density lipoprotein: a novel way to reduce nonalcoholic steatohepatitis in mice. Hepatology 56, 894–903 (2012).

    CAS  PubMed  Google Scholar 

  99. Bieghs, V. et al. The cholesterol derivative 27-hydroxycholesterol reduces steatohepatitis in mice. Gastroenterology 144, 167–178 (2013).

    CAS  PubMed  Google Scholar 

  100. Pan, X. et al. Adipogenic changes of hepatocytes in a high-fat diet-induced fatty liver mice model and non-alcoholic fatty liver disease patients. Endocrine 48, 834–847 (2015).

    CAS  PubMed  Google Scholar 

  101. Canbay, A. et al. Kupffer cell engulfment of apoptotic bodies stimulates death ligand and cytokine expression. Hepatology 38, 1188–1198 (2003).

    CAS  PubMed  Google Scholar 

  102. Miller, Y. I. et al. Oxidation-specific epitopes are danger-associated molecular patterns recognized by pattern recognition receptors of innate immunity. Circ. Res. 108, 235–248 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Bartneck, M. et al. Histidine-rich glycoprotein promotes macrophage activation and inflammation in chronic liver disease. Hepatology 63, 1310–1324 (2016).

    CAS  PubMed  Google Scholar 

  104. Hirsova, P. et al. Lipid-induced signaling causes release of inflammatory extracellular vesicles from hepatocytes. Gastroenterology 150, 956–967 (2016).

    CAS  PubMed  Google Scholar 

  105. Tomita, K. et al. CXCL10-mediates macrophage, but not other innate immune cells-associated inflammation in murine nonalcoholic steatohepatitis. Sci. Rep. 6, 28786 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Ibrahim, S. H. et al. Mixed lineage kinase 3 mediates release of C-X-C motif ligand 10-bearing chemotactic extracellular vesicles from lipotoxic hepatocytes. Hepatology 63, 731–744 (2016).

    CAS  PubMed  Google Scholar 

  107. Cannito, S. et al. Microvesicles released from fat-laden cells promote activation of hepatocellular NLRP3 inflammasome: a pro-inflammatory link between lipotoxicity and non-alcoholic steatohepatitis. PLOS ONE 12, e0172575 (2017).

    PubMed  PubMed Central  Google Scholar 

  108. Di Naso, F. C. et al. Obesity depresses the anti-inflammatory HSP70 pathway, contributing to NAFLD progression. Obesity 23, 120–129 (2015).

    PubMed  Google Scholar 

  109. Fujita, N. & Takei, Y. Iron overload in nonalcoholic steatohepatitis. Adv. Clin. Chem. 55, 105–132 (2011).

    CAS  PubMed  Google Scholar 

  110. Otogawa, K. et al. Erythrophagocytosis by liver macrophages (Kupffer cells) promotes oxidative stress, inflammation, and fibrosis in a rabbit model of steatohepatitis: implications for the pathogenesis of human nonalcoholic steatohepatitis. Am. J. Pathol. 170, 967–980 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Fujita, N. et al. Iron overload is associated with hepatic oxidative damage to DNA in nonalcoholic steatohepatitis. Cancer Epidemiol. Biomarkers Prev. 18, 424–432 (2009).

    CAS  PubMed  Google Scholar 

  112. Handa, P. et al. Iron overload results in hepatic oxidative stress, immune cell activation, and hepatocellular ballooning injury, leading to nonalcoholic steatohepatitis in genetically obese mice. Am. J. Physiol. Gastrointest. Liver Physiol. 310, G117–G127 (2016).

    PubMed  Google Scholar 

  113. Tomita, K. et al. Tumour necrosis factor α signalling through activation of Kupffer cells plays an essential role in liver fibrosis of non-alcoholic steatohepatitis in mice. Gut 55, 415–424 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Carter-Kent, C., Zein, N. N. & Feldstein, A. E. Cytokines in the pathogenesis of fatty liver and disease progression to steatohepatitis: implications for treatment. Am. J. Gastroenterol. 103, 1036–1042 (2008).

    CAS  PubMed  Google Scholar 

  115. De Taeye, B. M. et al. Macrophage TNF-α contributes to insulin resistance and hepatic steatosis in diet-induced obesity. Am. J. Physiol. Endocrinol. Metab. 293, E713–E725 (2007).

    PubMed  Google Scholar 

  116. Kodama, Y. et al. c-Jun N-terminal kinase-1 from hematopoietic cells mediates progression from hepatic steatosis to steatohepatitis and fibrosis in mice. Gastroenterology 137, 1467–1477 (2009).

    CAS  PubMed  Google Scholar 

  117. Dixon, L. J., Berk, M., Thapaliya, S., Papouchado, B. G. & Feldstein, A. E. Caspase-1-mediated regulation of fibrogenesis in diet-induced steatohepatitis. Lab. Invest. 92, 713–723 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Wree, A. et al. NLRP3 inflammasome activation is required for fibrosis development in NAFLD. J. Mol. Med. 92, 1069–1082 (2014).

    CAS  PubMed  Google Scholar 

  119. Pradere, J. P. et al. Hepatic macrophages but not dendritic cells contribute to liver fibrosis by promoting the survival of activated hepatic stellate cells in mice. Hepatology 58, 1461–1473 (2013).

    CAS  PubMed  Google Scholar 

  120. Negrin, K. A. et al. IL-1 signaling in obesity-induced hepatic lipogenesis and steatosis. PLOS ONE 9, e107265 (2014).

    PubMed  PubMed Central  Google Scholar 

  121. Tencerova, M. et al. Activated Kupffer cells inhibit insulin sensitivity in obese mice. FASEB J. 29, 2959–2969 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Mridha, A. R. et al. NLRP3 inflammasome blockade reduces liver inflammation and fibrosis in experimental NASH in mice. J. Hepatol. 66, 1037–1046 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Chen, L. et al. Selective depletion of hepatic Kupffer cells significantly alleviated hepatosteatosis and intrahepatic inflammation induced by high fat diet. Hepatogastroenterology 59, 1208–1212 (2012).

    CAS  PubMed  Google Scholar 

  124. Gambino, R., Musso, G. & Cassader, M. Redox balance in the pathogenesis of nonalcoholic fatty liver disease: mechanisms and therapeutic opportunities. Antioxid. Redox Signal. 15, 1325–1365 (2011).

    CAS  PubMed  Google Scholar 

  125. Malaguarnera, L. et al. Chitotriosidase gene expression in Kupffer cells from patients with non-alcoholic fatty liver disease. Gut 55, 1313–1320 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Bae, Y. S. et al. Macrophages generate reactive oxygen species in response to minimally oxidized low-density lipoprotein: toll-like receptor 4- and spleen tyrosine kinase-dependent activation of NADPH oxidase 2. Circ. Res. 104, 210–218 (2009).

    CAS  PubMed  Google Scholar 

  127. Meng, T. et al. Propofol reduces lipopolysaccharide-induced, NADPH oxidase (NOX 2) mediated TNF-α and IL-6 production in macrophages. Clin. Dev. Immunol. 2013, 325481 (2013).

    PubMed  PubMed Central  Google Scholar 

  128. Asanuma, T. et al. Super paramagnetic iron oxide MRI shows defective Kupffer cell uptake function in non-alcoholic fatty liver disease. Gut 59, 258–266 (2010).

    CAS  PubMed  Google Scholar 

  129. Cheong, H. et al. Phagocytic function of Kupffer cells in mouse nonalcoholic fatty liver disease models: evaluation with superparamagnetic iron oxide. J. Magn. Reson. Imaging 41, 1218–1227 (2015).

    PubMed  Google Scholar 

  130. Tonan, T. et al. CD14 expression and Kupffer cell dysfunction in non-alcoholic steatohepatitis: superparamagnetic iron oxide-magnetic resonance image and pathologic correlation. J. Gastroenterol. Hepatol. 27, 789–796 (2012).

    CAS  PubMed  Google Scholar 

  131. Schaffler, A., Scholmerich, J. & Buchler, C. Mechanisms of disease: adipocytokines and visceral adipose tissue — emerging role in nonalcoholic fatty liver disease. Nat. Clin. Pract. Gastroenterol. Hepatol. 2, 273–280 (2005).

    PubMed  Google Scholar 

  132. Asghar, A. & Sheikh, N. Role of immune cells in obesity induced low grade inflammation and insulin resistance. Cell. Immunol. 315, 18–26 (2017).

    CAS  PubMed  Google Scholar 

  133. Fuentes, L., Roszer, T. & Ricote, M. Inflammatory mediators and insulin resistance in obesity: role of nuclear receptor signaling in macrophages. Mediators Inflamm. 2010, 219583 (2010).

    PubMed  PubMed Central  Google Scholar 

  134. Bugianesi, E. et al. Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: sites and mechanisms. Diabetologia 48, 634–642 (2005).

    CAS  PubMed  Google Scholar 

  135. Stanton, M. C. et al. Inflammatory signals shift from adipose to liver during high fat feeding and influence the development of steatohepatitis in mice. J. Inflamm. 8, 8 (2011).

    CAS  Google Scholar 

  136. Bijnen, M. et al. Adipose tissue macrophages induce hepatic neutrophil recruitment and macrophage accumulation in mice. Gut 67, 1317–1327 (2018). This comprehensive study demonstrates that adipose tissue macrophages contribute to increased hepatic neutrophil and macrophage infiltration and worsening liver damage, emphasizing the role of adipose tissue–liver crosstalk in obesity and NAFLD.

    CAS  PubMed  Google Scholar 

  137. du Plessis, J. et al. Association of adipose tissue inflammation with histologic severity of nonalcoholic fatty liver disease. Gastroenterology 149, 635–648 (2015).

    PubMed  Google Scholar 

  138. Cancello, R. et al. Increased infiltration of macrophages in omental adipose tissue is associated with marked hepatic lesions in morbid human obesity. Diabetes 55, 1554–1561 (2006).

    CAS  PubMed  Google Scholar 

  139. Tordjman, J. et al. Structural and inflammatory heterogeneity in subcutaneous adipose tissue: relation with liver histopathology in morbid obesity. J. Hepatol. 56, 1152–1158 (2012).

    PubMed  Google Scholar 

  140. Tordjman, J. et al. Association between omental adipose tissue macrophages and liver histopathology in morbid obesity: influence of glycemic status. J. Hepatol. 51, 354–362 (2009).

    CAS  PubMed  Google Scholar 

  141. Polyzos, S. A., Kountouras, J. & Mantzoros, C. S. Leptin in nonalcoholic fatty liver disease: a narrative review. Metabolism 64, 60–78 (2015).

    CAS  PubMed  Google Scholar 

  142. Gatselis, N. K., Ntaios, G., Makaritsis, K. & Dalekos, G. N. Adiponectin: a key playmaker adipocytokine in non-alcoholic fatty liver disease. Clin. Exp. Med. 14, 121–131 (2014).

    CAS  PubMed  Google Scholar 

  143. Metlakunta, A. et al. Kupffer cells facilitate the acute effects of leptin on hepatic lipid metabolism. Am. J. Physiol. Endocrinol. Metab. 312, E11–E18 (2017).

    PubMed  Google Scholar 

  144. Chatterjee, S. et al. Leptin is key to peroxynitrite-mediated oxidative stress and Kupffer cell activation in experimental non-alcoholic steatohepatitis. J. Hepatol. 58, 778–784 (2013). This mouse study suggests that leptin activates Kupffer cells in NASH.

    CAS  PubMed  Google Scholar 

  145. Shen, J., Sakaida, I., Uchida, K., Terai, S. & Okita, K. Leptin enhances TNF-α production via p38 and JNK MAPK in LPS-stimulated Kupffer cells. Life Sci. 77, 1502–1515 (2005).

    CAS  PubMed  Google Scholar 

  146. Imajo, K. et al. Hyperresponsivity to low-dose endotoxin during progression to nonalcoholic steatohepatitis is regulated by leptin-mediated signaling. Cell Metab. 16, 44–54 (2012).

    CAS  PubMed  Google Scholar 

  147. Ikejima, K. et al. Leptin receptor-mediated signaling regulates hepatic fibrogenesis and remodeling of extracellular matrix in the rat. Gastroenterology 122, 1399–1410 (2002).

    CAS  PubMed  Google Scholar 

  148. Wang, J. et al. Kupffer cells mediate leptin-induced liver fibrosis. Gastroenterology 137, 713–723 (2009).

    CAS  PubMed  Google Scholar 

  149. De Minicis, S. et al. Reduced nicotinamide adenine dinucleotide phosphate oxidase mediates fibrotic and inflammatory effects of leptin on hepatic stellate cells. Hepatology 48, 2016–2026 (2008).

    PubMed  Google Scholar 

  150. Saxena, N. K., Ikeda, K., Rockey, D. C., Friedman, S. L. & Anania, F. A. Leptin in hepatic fibrosis: evidence for increased collagen production in stellate cells and lean littermates of ob/ob mice. Hepatology 35, 762–771 (2002).

    CAS  PubMed  Google Scholar 

  151. Huang, H., Park, P. H., McMullen, M. R. & Nagy, L. E. Mechanisms for the anti-inflammatory effects of adiponectin in macrophages. J. Gastroenterol. Hepatol. 23, S50–S53 (2008).

    CAS  PubMed  Google Scholar 

  152. Tsatsanis, C. et al. Adiponectin induces TNF-α and IL-6 in macrophages and promotes tolerance to itself and other pro-inflammatory stimuli. Biochem. Biophys. Res. Commun. 335, 1254–1263 (2005).

    CAS  PubMed  Google Scholar 

  153. Fukushima, J. et al. Adiponectin prevents progression of steatohepatitis in mice by regulating oxidative stress and Kupffer cell phenotype polarization. Hepatol. Res. 39, 724–738 (2009). This study demonstrates that adiponectin shifts Kupffer cell polarization towards the anti-inflammatory phenotype, suggesting beneficial effects of adiponectin on macrophages.

    CAS  PubMed  Google Scholar 

  154. Luo, N. et al. Enhanced adiponectin actions by overexpression of adiponectin receptor 1 in macrophages. Atherosclerosis 228, 124–135 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Robert, O. et al. Decreased expression of the glucocorticoid receptor-GILZ pathway in Kupffer cells promotes liver inflammation in obese mice. J. Hepatol. 64, 916–924 (2016).

    CAS  PubMed  Google Scholar 

  156. Ho, M. K. & Springer, T. A. Mac-1 antigen: quantitative expression in macrophage populations and tissues, and immunofluorescent localization in spleen. J. Immunol. 128, 2281–2286 (1982).

    CAS  PubMed  Google Scholar 

  157. Traber, P. G. & Zomer, E. Therapy of experimental NASH and fibrosis with galectin inhibitors. PLOS ONE 8, e83481 (2013).

    PubMed  PubMed Central  Google Scholar 

  158. Harrison, S. A. et al. Randomised clinical study: GR-MD-02, a galectin-3 inhibitor, versus placebo in patients having non-alcoholic steatohepatitis with advanced fibrosis. Aliment. Pharmacol. Ther. 44, 1183–1198 (2016). This phase I clinical trial suggests that targeting macrophages via galectin 3 shows promise as a treatment option for NASH.

    CAS  PubMed  Google Scholar 

  159. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02421094 (2017).

  160. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02462967 (2018).

  161. Lefebvre, E. et al. Antifibrotic effects of the dual CCR2/CCR5 antagonist cenicriviroc in animal models of liver and kidney fibrosis. PLOS ONE 11, e0158156 (2016).

    PubMed  PubMed Central  Google Scholar 

  162. Friedman, S. L. et al. A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis. Hepatology 67, 1754–1767 (2018). This phase II trial of a CCR2–CCR5 inhibitor suppressing monocyte recruitment demonstrates fibrosis improvement in patients with NASH.

    CAS  PubMed  Google Scholar 

  163. Marra, F. & Tacke, F. Roles for chemokines in liver disease. Gastroenterology 147, 577–594 (2014).

    CAS  PubMed  Google Scholar 

  164. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03028740 (2018).

  165. Neuschwander-Tetri, B. A. et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 385, 956–965 (2015).

    CAS  PubMed  Google Scholar 

  166. Yao, J. et al. FXR agonist GW4064 alleviates endotoxin-induced hepatic inflammation by repressing macrophage activation. World J. Gastroenterol. 20, 14430–14441 (2014).

    PubMed  PubMed Central  Google Scholar 

  167. McMahan, R. H. et al. Bile acid receptor activation modulates hepatic monocyte activity and improves nonalcoholic fatty liver disease. J. Biol. Chem. 288, 11761–11770 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02548351 (2018).

  169. Eguchi, Y. et al. Pilot study of liraglutide effects in non-alcoholic steatohepatitis and non-alcoholic fatty liver disease with glucose intolerance in Japanese patients (LEAN-J). Hepatol. Res. 45, 269–278 (2015).

    CAS  PubMed  Google Scholar 

  170. Wang, X. C., Gusdon, A. M., Liu, H. & Qu, S. Effects of glucagon-like peptide-1 receptor agonists on non-alcoholic fatty liver disease and inflammation. World J. Gastroenterol. 20, 14821–14830 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Armstrong, M. J. et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet 387, 679–690 (2016).

    CAS  PubMed  Google Scholar 

  172. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02970942 (2018).

  173. Wang, Y. et al. Exendin-4 decreases liver inflammation and atherosclerosis development simultaneously by reducing macrophage infiltration. Br. J. Pharmacol. 171, 723–734 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Yamamoto, T. et al. Glucagon-like peptide-1 analogue prevents nonalcoholic steatohepatitis in non-obese mice. World J. Gastroenterol. 22, 2512–2523 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. Feng, X. et al. Chrysin attenuates inflammation by regulating M1/M2 status via activating PPARγ. Biochem. Pharmacol. 89, 503–514 (2014).

    CAS  PubMed  Google Scholar 

  176. Luo, W., Xu, Q., Wang, Q., Wu, H. & Hua, J. Effect of modulation of PPAR-γ activity on Kupffer cells M1/M2 polarization in the development of non-alcoholic fatty liver disease. Sci. Rep. 7, 44612 (2017).

    PubMed  PubMed Central  Google Scholar 

  177. Odegaard, J. I. et al. Macrophage-specific PPARγ controls alternative activation and improves insulin resistance. Nature 447, 1116–1120 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  178. Boettcher, E., Csako, G., Pucino, F., Wesley, R. & Loomba, R. Meta-analysis: pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis. Aliment. Pharmacol. Ther. 35, 66–75 (2012).

    CAS  PubMed  Google Scholar 

  179. Cusi, K. et al. Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial. Ann. Intern. Med. 165, 305–315 (2016).

    PubMed  Google Scholar 

  180. He, S. et al. Pioglitazone prescription increases risk of bladder cancer in patients with type 2 diabetes: an updated meta-analysis. Tumour Biol. 35, 2095–2102 (2014).

    CAS  PubMed  Google Scholar 

  181. Staels, B. et al. Hepatoprotective effects of the dual peroxisome proliferator-activated receptor α/δ agonist, GFT505, in rodent models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Hepatology 58, 1941–1952 (2013).

    CAS  PubMed  Google Scholar 

  182. Ratziu, V. et al. Elafibranor, an agonist of the peroxisome proliferator-activated receptor-α and -δ, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology 150, 1147–1159 (2016).

    CAS  PubMed  Google Scholar 

  183. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02704403 (2018).

  184. Zeng, T., Zhang, C. L., Zhao, X. L. & Xie, K. Q. Pentoxifylline for the treatment of nonalcoholic fatty liver disease: a meta-analysis of randomized double-blind, placebo-controlled studies. Eur. J. Gastroenterol. Hepatol. 26, 646–653 (2014).

    CAS  PubMed  Google Scholar 

  185. Loomba, R. et al. The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: a randomized, phase 2 trial. Hepatology 67, 549–559 (2017).

    PubMed  Google Scholar 

  186. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03053063 (2018).

  187. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03053050 (2018).

  188. Handberg, A. et al. Plasma sCD36 is associated with markers of atherosclerosis, insulin resistance and fatty liver in a nondiabetic healthy population. J. Intern. Med. 271, 294–304 (2012).

    CAS  PubMed  Google Scholar 

  189. Ogawa, Y. et al. Soluble CD14 levels reflect liver inflammation in patients with nonalcoholic steatohepatitis. PLOS ONE 8, e65211 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  190. Holland-Fischer, P. et al. Kupffer cells are activated in cirrhotic portal hypertension and not normalised by TIPS. Gut 60, 1389–1393 (2011).

    CAS  PubMed  Google Scholar 

  191. Kazankov, K. et al. Soluble CD163, a macrophage activation marker, is independently associated with fibrosis in patients with chronic viral hepatitis B and C. Hepatology 60, 521–530 (2014).

    CAS  PubMed  Google Scholar 

  192. Sandahl, T. D. et al. Hepatic macrophage activation and the LPS pathway in patients with alcoholic hepatitis: a prospective cohort study. Am. J. Gastroenterol. 109, 1749–1756 (2014).

    CAS  PubMed  Google Scholar 

  193. Gronbaek, H. et al. Macrophage activation markers predict mortality in patients with liver cirrhosis without or with acute-on-chronic liver failure (ACLF). J. Hepatol. 64, 813–822 (2016).

    PubMed  Google Scholar 

  194. Kazankov, K. et al. The macrophage activation marker sCD163 is associated with changes in NAFLD and metabolic profile during lifestyle intervention in obese children. Pediatr. Obes. 10, 226–233 (2015).

    CAS  PubMed  Google Scholar 

  195. Kazankov, K. et al. The macrophage activation marker sCD163 is associated with morphological disease stages in patients with non-alcoholic fatty liver disease. Liver Int. 36, 1549–1557 (2016). This study suggests that the specific macrophage marker soluble CD163 might be a good biomarker for the severity of NAFLD.

    CAS  PubMed  Google Scholar 

  196. Mueller, J. L. et al. Circulating soluble CD163 is associated with steatohepatitis and advanced fibrosis in nonalcoholic fatty liver disease. Clin. Transl Gastroenterol. 6, e114 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  197. Kazankov, K. et al. Macrophage activation marker soluble CD163 and non-alcoholic fatty liver disease in morbidly obese patients undergoing bariatric surgery. J. Gastroenterol. Hepatol. 30, 1293–1300 (2015).

    CAS  PubMed  Google Scholar 

  198. Moller, H. J., Frikke-Schmidt, R., Moestrup, S. K., Nordestgaard, B. G. & Tybjaerg-Hansen, A. Serum soluble CD163 predicts risk of type 2 diabetes in the general population. Clin. Chem. 57, 291–297 (2011).

    PubMed  Google Scholar 

  199. Kornek, M. et al. Circulating microparticles as disease-specific biomarkers of severity of inflammation in patients with hepatitis C or nonalcoholic steatohepatitis. Gastroenterology 143, 448–458 (2012).

    CAS  PubMed  Google Scholar 

  200. Chalasani, N. et al. The diagnosis and management of NAFLD: practice guidance from the American Association for the Study of Liver Diseases. Hepatology 67, 328–357 (2018). This is the latest clinical practice guideline for nonalcoholic fatty liver disease from the American Association for the Study of Liver Diseases.

    PubMed  Google Scholar 

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Acknowledgements

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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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.

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Correspondence to Konstantin Kazankov.

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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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Kazankov, K., Jørgensen, S.M.D., Thomsen, K.L. et al. The role of macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Nat Rev Gastroenterol Hepatol 16, 145–159 (2019). https://doi.org/10.1038/s41575-018-0082-x

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