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  • Review Article
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Triggering and resolution of inflammation in NASH

Nature Reviews Gastroenterology & Hepatology volume 15, pages 349–364 (2018)Cite this article

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Abstract

Nonalcoholic steatohepatitis (NASH) is considered the progressive form of nonalcoholic fatty liver disease (NAFLD) and is characterized by liver steatosis, inflammation, hepatocellular injury and different degrees of fibrosis. A central issue in this field relates to the identification of those factors that trigger inflammation, thus fuelling the transition from nonalcoholic fatty liver to NASH. These triggers of liver inflammation might have their origins outside the liver (such as in adipose tissue or the gut) as well as inside the organ (for instance, lipotoxicity, innate immune responses, cell death pathways, mitochondrial dysfunction and endoplasmic reticulum stress), both of which contribute to NASH development. In this Review, we summarize the currently available information on the key upstream triggers of inflammation in NASH. We further delineate the mechanisms by which liver inflammation is resolved and the implications of a defective pro-resolution process. A better knowledge of these mechanisms should help to design targeted therapies able to halt or reverse disease progression.

Key points

  • Triggers of hepatic inflammation have their origins outside as well as inside the liver, and both pathways contribute to the transition from isolated steatosis to NASH.

  • Adipose tissue dysfunction and the hepatic inflammatory response have a fundamental role during NASH development.

  • Cellular and molecular response mechanisms also promote liver inflammation in the absence of a fatty liver by inducing a chronic inflammatory response that results in hepatocyte damage.

  • System biology approaches that integrate metabolomics, proteomics and epigenetic analysis are needed to unravel the molecular signatures of NASH.

  • Abrogation of liver inflammation could be achieved by exploiting active, physiological pro-resolving mechanisms (a ‘pushing for’ strategy) instead of the classical passive blockade of pro-inflammatory mediators (the ‘push back’ strategy).

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Fig. 1: Triggering and resolution of NASH.
Fig. 2: Intrahepatic crosstalk in the setting of NASH progression.
Fig. 3: Mechanism of resolution of inflammation in NASH.

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References

  1. Brunt, E. M. et al. Nonalcoholic fatty liver disease. Nat. Rev. Dis. Primers 1, 15080 (2015).

    Article  PubMed  Google Scholar 

  2. Bedossa, P. Pathology of non-alcoholic fatty liver disease. Liver Int. 37 (Suppl. 1), 85–89 (2017).

    Article  PubMed  Google Scholar 

  3. Younossi, Z. M. et al. Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 64, 73–84 (2016).

    Article  PubMed  Google Scholar 

  4. Marengo, A., Jouness, R. I. & Bugianesi, E. Progression and natural history of nonalcoholic fatty liver disease in adults. Clin. Liver Dis. 20, 313–324 (2016).

    Article  PubMed  Google Scholar 

  5. Goh, G. B. & McCullough, A. J. Natural history of nonalcoholic fatty liver disease. Dig. Dis. Sci. 61, 1226–1233 (2016).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  6. Hardy, T., Oakley, F., Anstee, Q. M. & Day, C. P. Nonalcoholic fatty liver disease: pathogenesis and disease spectrum. Annu. Rev. Pathol. 11, 451–496 (2016).

    Article  PubMed  CAS  Google Scholar 

  7. Machado, M. V. & Diehl, A. M. Pathogenesis of nonalcoholic steatohepatitis. Gastroenterology 150, 1769–1777 (2016).

    Article  PubMed  CAS  Google Scholar 

  8. Koyama, Y. & Brenner, D. A. Liver inflammation and fibrosis. J. Clin. Invest. 127, 55–64 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Lee, Y. A., Wallace, M. C. & Friedman, S. L. Pathobiology of liver fibrosis: a translational success story. Gut 64, 830–841 (2015).

    Article  PubMed  CAS  Google Scholar 

  10. Argo, C. K., Northup, P. G., Al-Osaimi, A. M. & Caldwell, S. H. Systematic review of risk factors for fibrosis progression in non-alcoholic steatohepatitis. J. Hepatol. 51, 371–379 (2009).

    Article  PubMed  CAS  Google Scholar 

  11. Hagstrom, H. et al. Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD. J. Hepatol. 67, 1265–1273 (2017).

    Article  PubMed  Google Scholar 

  12. Filozof, C. et al. Clinical endpoints and adaptive clinical trials in precirrhotic nonalcoholic steatohepatitis: facilitating development approaches for an emerging epidemic. Hepatol. Commun. 1, 577–585 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Kawano, Y. & Cohen, D. E. Mechanisms of hepatic triglyceride accumulation in non-alcoholic fatty liver disease. J. Gastroenterol. 48, 434–441 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  15. Bray, G. A., Nielsen, S. J. & Popkin, B. M. Consumption of high-fructose corn syrup in beverages may play a role in the epidemic of obesity. Am. J. Clin. Nutr. 79, 537–543 (2004).

    Article  PubMed  CAS  Google Scholar 

  16. Barquera, S. et al. Energy intake from beverages is increasing among Mexican adolescents and adults. J. Nutr. 138, 2454–2461 (2008).

    Article  PubMed  CAS  Google Scholar 

  17. Duffey, K. J. & Popkin, B. M. Shifts in patterns and consumption of beverages between 1965 and 2002. Obesity 15, 2739–2747 (2007).

    Article  PubMed  Google Scholar 

  18. Yang, Z. H., Miyahara, H., Takeo, J. & Katayama, M. Diet high in fat and sucrose induces rapid onset of obesity-related metabolic syndrome partly through rapid response of genes involved in lipogenesis, insulin signalling and inflammation in mice. Diabetol Metab. Syndr. 4, 32 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Liu, J. et al. Toll-like receptor-4 signalling in the progression of non-alcoholic fatty liver disease induced by high-fat and high-fructose diet in mice. Clin. Exp. Pharmacol. Physiol. 41, 482–488 (2014).

    Article  PubMed  CAS  Google Scholar 

  20. Crescenzo, R. et al. Increased hepatic de novo lipogenesis and mitochondrial efficiency in a model of obesity induced by diets rich in fructose. Eur. J. Nutr. 52, 537–545 (2013).

    Article  PubMed  CAS  Google Scholar 

  21. Rebollo, A. et al. Liquid fructose downregulates Sirt1 expression and activity and impairs the oxidation of fatty acids in rat and human liver cells. Biochim. Biophys. Acta 1841, 514–524 (2014).

    Article  PubMed  CAS  Google Scholar 

  22. Teff, K. L. et al. Dietary fructose reduces circulating insulin and leptin, attenuates postprandial suppression of ghrelin, and increases triglycerides in women. J. Clin. Endocrinol. Metab. 89, 2963–2972 (2004).

    Article  PubMed  CAS  Google Scholar 

  23. Charlton, M. et al. Fast food diet mouse: novel small animal model of NASH with ballooning, progressive fibrosis, and high physiological fidelity to the human condition. Am. J. Physiol. Gastrointest. Liver Physiol. 301, G825–G834 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Dupas, J. et al. Progressive induction of type 2 diabetes: effects of a reality-like fructose enriched diet in young wistar rats. PLOS ONE 11, e0146821 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Kawasaki, T. et al. Rats fed fructose-enriched diets have characteristics of nonalcoholic hepatic steatosis. J. Nutr. 139, 2067–2071 (2009).

    Article  PubMed  CAS  Google Scholar 

  26. Ren, L. P. et al. Differing endoplasmic reticulum stress response to excess lipogenesis versus lipid oversupply in relation to hepatic steatosis and insulin resistance. PLOS ONE 7, e30816 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Sapp, V., Gaffney, L., EauClaire, S. F. & Matthews, R. P. Fructose leads to hepatic steatosis in zebrafish that is reversed by mechanistic target of rapamycin (mTOR) inhibition. Hepatology 60, 1581–1592 (2014).

    Article  PubMed  CAS  Google Scholar 

  28. 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).

    Article  PubMed  CAS  Google Scholar 

  29. Rosas-Villegas, A. et al. Differential effect of sucrose and fructose in combination with a high fat diet on intestinal microbiota and kidney oxidative stress. Nutrients 9, pii: E393 (2017).

  30. Kavanagh, K. et al. Dietary fructose induces endotoxemia and hepatic injury in calorically controlled primates. Am. J. Clin. Nutr. 98, 349–357 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Aigner, E., Weiss, G. & Datz, C. Dysregulation of iron and copper homeostasis in nonalcoholic fatty liver. World J. Hepatol. 7, 177–188 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Aigner, E. et al. Copper availability contributes to iron perturbations in human nonalcoholic fatty liver disease. Gastroenterology 135, 680–688 (2008).

    Article  PubMed  CAS  Google Scholar 

  33. Nelson, J. E., Klintworth, H. & Kowdley, K. V. Iron metabolism in nonalcoholic fatty liver disease. Curr. Gastroenterol. Rep. 14, 8–16 (2012).

    Article  PubMed  Google Scholar 

  34. Ceccarelli, D., Gallesi, D., Giovannini, F., Ferrali, M. & Masini, A. Relationship between free iron level and rat liver mitochondrial dysfunction in experimental dietary iron overload. Biochem. Biophys. Res. Commun. 209, 53–59 (1995).

    Article  PubMed  CAS  Google Scholar 

  35. Galaris, D. & Pantopoulos, K. Oxidative stress and iron homeostasis: mechanistic and health aspects. Crit. Rev. Clin. Lab Sci. 45, 1–23 (2008).

    Article  PubMed  CAS  Google Scholar 

  36. Dixon, S. J. & Stockwell, B. R. The role of iron and reactive oxygen species in cell death. Nat. Chem. Biol. 10, 9–17 (2014).

    Article  PubMed  CAS  Google Scholar 

  37. Britton, L. J., Subramaniam, V. N. & Crawford, D. H. Iron and non-alcoholic fatty liver disease. World J. Gastroenterol. 22, 8112–8122 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. al-Othman, A. A., Rosenstein, F. & Lei, K. Y. Copper deficiency alters plasma pool size, percent composition and concentration of lipoprotein components in rats. J. Nutr. 122, 1199–1204 (1992).

    Article  PubMed  CAS  Google Scholar 

  39. al-Othman, A. A., Rosenstein, F. & Lei, K. Y. Copper deficiency increases in vivo hepatic synthesis of fatty acids, triacylglycerols, and phospholipids in rats. Proc. Soc. Exp. Biol. Med. 204, 97–103 (1993).

    Article  PubMed  CAS  Google Scholar 

  40. Stattermayer, A. F. et al. Low hepatic copper content and PNPLA3 polymorphism in non-alcoholic fatty liver disease in patients without metabolic syndrome. J. Trace Elem. Med. Biol. 39, 100–107 (2017).

    Article  PubMed  CAS  Google Scholar 

  41. Aigner, E. et al. A role for low hepatic copper concentrations in nonalcoholic fatty liver disease. Am. J. Gastroenterol. 105, 1978–1985 (2010).

    Article  PubMed  CAS  Google Scholar 

  42. Tallino, S. et al. Nutrigenomics analysis reveals that copper deficiency and dietary sucrose up-regulate inflammation, fibrosis and lipogenic pathways in a mature rat model of nonalcoholic fatty liver disease. J. Nutr. Biochem. 26, 996–1006 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Leamy, A. K., Egnatchik, R. A. & Young, J. D. Molecular mechanisms and the role of saturated fatty acids in the progression of non-alcoholic fatty liver disease. Prog. Lipid Res. 52, 165–174 (2013).

    Article  PubMed  CAS  Google Scholar 

  44. Alisi, A. et al. Relationship between portal chronic inflammation and disease severity in paediatric non-alcoholic fatty liver disease. Dig. Liver Dis. 43, 143–146 (2011).

    Article  PubMed  Google Scholar 

  45. Enjoji, M., Yasutake, K., Kohjima, M. & Nakamuta, M. Nutrition and nonalcoholic fatty liver disease: the significance of cholesterol. Int. J. Hepatol. 2012, 925807 (2012).

    PubMed  PubMed Central  Google Scholar 

  46. Arguello, G., Balboa, E., Arrese, M. & Zanlungo, S. Recent insights on the role of cholesterol in non-alcoholic fatty liver disease. Biochim. Biophys. Acta 1852, 1765–1778 (2015).

    Article  PubMed  CAS  Google Scholar 

  47. Puri, P. et al. A lipidomic analysis of nonalcoholic fatty liver disease. Hepatology 46, 1081–1090 (2007).

    Article  PubMed  CAS  Google Scholar 

  48. Min, H. K. et al. Increased hepatic synthesis and dysregulation of cholesterol metabolism is associated with the severity of nonalcoholic fatty liver disease. Cell Metab. 15, 665–674 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Al-Rasadi, K., Rizzo, M., Montalto, G. & Berg, G. Nonalcoholic fatty liver disease, cardiovascular risk, and carotid inflammation. Angiology 66, 601–603 (2015).

    Article  PubMed  CAS  Google Scholar 

  50. Arrese, M. & Karpen, S. J. Nuclear receptors, inflammation, and liver disease: insights for cholestatic and fatty liver diseases. Clin. Pharmacol. Ther. 87, 473–478 (2010).

    Article  PubMed  CAS  Google Scholar 

  51. Asrih, M. & Jornayvaz, F. R. Inflammation as a potential link between nonalcoholic fatty liver disease and insulin resistance. J. Endocrinol. 218, R25–R36 (2013).

    Article  PubMed  CAS  Google Scholar 

  52. Wouters, K. et al. Dietary cholesterol, rather than liver steatosis, leads to hepatic inflammation in hyperlipidemic mouse models of nonalcoholic steatohepatitis. Hepatology 48, 474–486 (2008).

    Article  PubMed  Google Scholar 

  53. Das, U. N. Biological significance of essential fatty acids. J. Assoc. Physicians India 54, 309–319 (2006).

    PubMed  CAS  Google Scholar 

  54. Seki, H., Tani, Y. & Arita, M. Omega-3 PUFA derived anti-inflammatory lipid mediator resolvin E. Prostaglandins Other Lipid Mediat. 89, 126–130 (2009).

    Article  PubMed  CAS  Google Scholar 

  55. Araya, J. et al. Increase in long-chain polyunsaturated fatty acid n - 6/n - 3 ratio in relation to hepatic steatosis in patients with non-alcoholic fatty liver disease. Clin. Sci. 106, 635–643 (2004).

    Article  CAS  Google Scholar 

  56. Argo, C. K. et al. Effects of n-3 fish oil on metabolic and histological parameters in NASH: a double-blind, randomized, placebo-controlled trial. J. Hepatol. 62, 190–197 (2015).

    Article  PubMed  CAS  Google Scholar 

  57. He, X. X. et al. Effectiveness of Omega-3 polyunsaturated fatty acids in non-alcoholic fatty liver disease: a meta-analysis of randomized controlled trials. PLOS ONE 11, e0162368 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Feldstein, A. E. et al. Mass spectrometric profiling of oxidized lipid products in human nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. J. Lipid Res. 51, 3046–3054 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Santoro, N. et al. Oxidized fatty acids: a potential pathogenic link between fatty liver and type 2 diabetes in obese adolescents? Antioxid. Redox Signal 20, 383–389 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Dongiovanni, P., Rametta, R., Meroni, M. & Valenti, L. The role of insulin resistance in nonalcoholic steatohepatitis and liver disease development — a potential therapeutic target? Expert Rev. Gastroenterol. Hepatol. 10, 229–242 (2016).

    Article  PubMed  CAS  Google Scholar 

  61. Masarone, M. et al. Liver biopsy in type 2 diabetes mellitus: steatohepatitis represents the sole feature of liver damage. PLOS ONE 12, e0178473 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Bieghs, V. et al. LDL receptor knock-out mice are a physiological model particularly vulnerable to study the onset of inflammation in non-alcoholic fatty liver disease. PLOS ONE 7, e30668 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Cortez-Pinto, H., Camilo, M. E., Baptista, A., De Oliveira, A. G. & De Moura, M. C. Non-alcoholic fatty liver: another feature of the metabolic syndrome? Clin. Nutr. 18, 353–358 (1999).

    Article  PubMed  CAS  Google Scholar 

  64. Balato, N. et al. Nonalcoholic fatty liver disease, spleen and psoriasis: new aspects of low-grade chronic inflammation. World J. Gastroenterol. 21, 6892–6897 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  65. van der Poorten, D. & George, J. Disease-specific mechanisms of fibrosis: hepatitis C virus and nonalcoholic steatohepatitis. Clin. Liver Dis. 12, 805–824, ix (2008).

    Article  PubMed  Google Scholar 

  66. 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).

    Article  CAS  Google Scholar 

  67. 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).

    Article  PubMed  CAS  Google Scholar 

  68. Esser, N., Legrand-Poels, S., Piette, J., Scheen, A. J. & Paquot, N. Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes. Diabetes Res. Clin. Pract. 105, 141–150 (2014).

    Article  PubMed  CAS  Google Scholar 

  69. Lumeng, C. N., Bodzin, J. L. & Saltiel, A. R. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J. Clin. Invest. 117, 175–184 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Lanthier, N. et al. Kupffer cell depletion prevents but has no therapeutic effect on metabolic and inflammatory changes induced by a high-fat diet. FASEB J 25, 4301–4311 (2011).

    Article  PubMed  CAS  Google Scholar 

  71. Panee, J. Monocyte chemoattractant protein 1 (MCP-1) in obesity and diabetes. Cytokine 60, 1–12 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Maximos, M. et al. The role of liver fat and insulin resistance as determinants of plasma aminotransferase elevation in nonalcoholic fatty liver disease. Hepatology 61, 153–160 (2015).

    Article  PubMed  CAS  Google Scholar 

  73. Lomonaco, R. et al. Effect of adipose tissue insulin resistance on metabolic parameters and liver histology in obese patients with nonalcoholic fatty liver disease. Hepatology 55, 1389–1397 (2012).

    Article  PubMed  CAS  Google Scholar 

  74. Rotman, Y. & Neuschwander-Tetri, B. A. Liver fat accumulation as a barometer of insulin responsiveness again points to adipose tissue as the culprit. Hepatology 65, 1088–1090 (2017).

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  76. Fabbrini, E. et al. Surgical removal of omental fat does not improve insulin sensitivity and cardiovascular risk factors in obese adults. Gastroenterology 139, 448–455 (2010).

    Article  PubMed  Google Scholar 

  77. Adolph, T. E., Grander, C., Grabherr, F. & Tilg, H. Adipokines and non-alcoholic fatty liver disease: multiple interactions. Int. J. Mol. Sci. 18, E1649 (2017).

    Article  PubMed  Google Scholar 

  78. Polyzos, S. A., Kountouras, J. & Mantzoros, C. S. Adipokines in nonalcoholic fatty liver disease. Metabolism 65, 1062–1079 (2016).

    Article  PubMed  CAS  Google Scholar 

  79. Buechler, C., Wanninger, J. & Neumeier, M. Adiponectin, a key adipokine in obesity related liver diseases. World J. Gastroenterol. 17, 2801–2811 (2011).

    PubMed  PubMed Central  CAS  Google Scholar 

  80. Hui, J. M. et al. Beyond insulin resistance in NASH: TNF-alpha or adiponectin? Hepatology 40, 46–54 (2004).

    Article  PubMed  CAS  Google Scholar 

  81. Wieckowska, A. et al. Increased hepatic and circulating interleukin-6 levels in human nonalcoholic steatohepatitis. Am. J. Gastroenterol. 103, 1372–1379 (2008).

    Article  PubMed  CAS  Google Scholar 

  82. Tsochatzis, E., Papatheodoridis, G. V. & Archimandritis, A. J. The evolving role of leptin and adiponectin in chronic liver diseases. Am. J. Gastroenterol. 101, 2629–2640 (2006).

    Article  PubMed  CAS  Google Scholar 

  83. Hendy, O. M. et al. Evaluation of circulating zonulin as a potential marker in the pathogenesis of nonalcoholic fatty liver disease. APMIS 125, 607–613 (2017).

    Article  PubMed  CAS  Google Scholar 

  84. Polyzos, S. A. et al. Circulating leptin in non-alcoholic fatty liver disease: a systematic review and meta-analysis. Diabetologia 59, 30–43 (2016).

    Article  PubMed  CAS  Google Scholar 

  85. Procaccini, C. et al. Leptin: the prototypic adipocytokine and its role in NAFLD. Curr. Pharm. Des. 16, 1902–1912 (2010).

    Article  PubMed  CAS  Google Scholar 

  86. Abu-Tair, L., Doron, S., Mahamid, M., Amer, J. & Safadi, R. Leptin modulates lymphocytes’ adherence to hepatic stellate cells is associated with oxidative status alterations. Mitochondrion 13, 473–480 (2013).

    Article  PubMed  CAS  Google Scholar 

  87. Brandl, K. & Schnabl, B. Intestinal microbiota and nonalcoholic steatohepatitis. Curr. Opin. Gastroenterol. 33, 128–133 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Boursier, J. et al. The severity of nonalcoholic fatty liver disease is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota. Hepatology 63, 764–775 (2016).

    Article  PubMed  CAS  Google Scholar 

  89. Farhadi, A. et al. Susceptibility to gut leakiness: a possible mechanism for endotoxaemia in non-alcoholic steatohepatitis. Liver Int. 28, 1026–1033 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  90. Csak, T. et al. Deficiency in myeloid differentiation factor-2 and toll-like receptor 4 expression attenuates nonalcoholic steatohepatitis and fibrosis in mice. Am. J. Physiol. Gastrointest. Liver Physiol. 300, G433–G441 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Etienne-Mesmin, L., Vijay-Kumar, M., Gewirtz, A. T. & Chassaing, B. Hepatocyte toll-like receptor 5 promotes bacterial clearance and protects mice against high-fat diet-induced liver disease. Cell. Mol. Gastroenterol. Hepatol. 2, 584–604 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  92. Schneider, K. M. et al. CX3CR1 is a gatekeeper for intestinal barrier integrity in mice: limiting steatohepatitis by maintaining intestinal homeostasis. Hepatology 62, 1405–1416 (2015).

    Article  PubMed  CAS  Google Scholar 

  93. Rahman, K. et al. Loss of junctional adhesion molecule A promotes severe steatohepatitis in mice on a diet high in saturated fat, fructose, and cholesterol. Gastroenterology 151, 733–746.e12 (2016).

    Article  PubMed  CAS  Google Scholar 

  94. Jiang, W. et al. Dysbiosis gut microbiota associated with inflammation and impaired mucosal immune function in intestine of humans with non-alcoholic fatty liver disease. Sci. Rep. 5, 8096 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Luck, H. et al. Regulation of obesity-related insulin resistance with gut anti-inflammatory agents. Cell Metab. 21, 527–542 (2015).

    Article  PubMed  CAS  Google Scholar 

  96. du Plessis, J. et al. Pro-inflammatory cytokines but not endotoxin-related parameters associate with disease severity in patients with NAFLD. PLOS ONE 11, e0166048 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Pang, J. et al. Significant positive association of endotoxemia with histological severity in 237 patients with non-alcoholic fatty liver disease. Aliment. Pharmacol. Ther. 46, 175–182 (2017).

    Article  PubMed  CAS  Google Scholar 

  98. Kitabatake, H. et al. Association between endotoxemia and histological features of nonalcoholic fatty liver disease. World J. Gastroenterol. 23, 712–722 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  99. Freudenberg, M. A., Freudenberg, N. & Galanos, C. Time course of cellular distribution of endotoxin in liver, lungs and kidneys of rats. Br. J. Exp. Pathol. 63, 56–65 (1982).

    PubMed  PubMed Central  CAS  Google Scholar 

  100. Albenberg, L. G. & Wu, G. D. Diet and the intestinal microbiome: associations, functions, and implications for health and disease. Gastroenterology 146, 1564–1572 (2014).

    Article  PubMed  CAS  Google Scholar 

  101. Arab, J. P., Karpen, S. J., Dawson, P. A., Arrese, M. & Trauner, M. Bile acids and nonalcoholic fatty liver disease: molecular insights and therapeutic perspectives. Hepatology 65, 350–362 (2017).

    Article  PubMed  Google Scholar 

  102. Chow, M. D., Lee, Y. H. & Guo, G. L. The role of bile acids in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Mol. Aspects Med. 56, 34–44 (2017).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  103. Ridlon, J. M., Kang, D. J., Hylemon, P. B. & Bajaj, J. S. Bile acids and the gut microbiome. Curr. Opin. Gastroenterol. 30, 332–338 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Jungst, C. et al. Intrahepatic cholestasis in common chronic liver diseases. Eur. J. Clin. Invest. 43, 1069–1083 (2013).

    Article  PubMed  Google Scholar 

  105. Pizarro, M. et al. Bile secretory function in the obese Zucker rat: evidence of cholestasis and altered canalicular transport function. Gut 53, 1837–1843 (2004).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Aranha, M. M. et al. Bile acid levels are increased in the liver of patients with steatohepatitis. Eur. J. Gastroenterol. Hepatol. 20, 519–525 (2008).

    Article  PubMed  CAS  Google Scholar 

  107. Cai, S. Y. & Boyer, J. L. Studies on the mechanisms of bile acid initiated hepatic inflammation in cholestatic liver injury. Inflamm. Cell Signal 4, pii: e1561 (2017).

  108. Li, M., Cai, S. Y. & Boyer, J. L. Mechanisms of bile acid mediated inflammation in the liver. Mol. Aspects Med. 56, 45–53 (2017).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  109. Puri, P. et al. The presence and severity of nonalcoholic steatohepatitis is associated with specific changes in circulating bile acids. Hepatology https://doi.org/10.1002/hep.29359 (2017).

  110. Jahn, D. & Geier, A. Bile acids in NASH: pathophysiological driving force or innocent bystanders? Hepatology 67, 464–466 (2017).

  111. Magee, N., Zou, A. & Zhang, Y. Pathogenesis of nonalcoholic steatohepatitis: interactions between liver parenchymal and nonparenchymal cells. Biomed. Res. Int. 2016, 5170402 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  112. Ikura, Y. et al. Localization of oxidized phosphatidylcholine in nonalcoholic fatty liver disease: impact on disease progression. Hepatology 43, 506–514 (2006).

    Article  PubMed  CAS  Google Scholar 

  113. Terman, A., Kurz, T., Gustafsson, B. & Brunk, U. T. Lysosomal labilization. IUBMB Life 58, 531–539 (2006).

    Article  PubMed  CAS  Google Scholar 

  114. Zhao, G. N. et al. Tmbim1 is a multivesicular body regulator that protects against non-alcoholic fatty liver disease in mice and monkeys by targeting the lysosomal degradation of Tlr4. Nat. Med. 23, 742–752 (2017).

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  116. Chatterjee, S. et al. P2X7 receptor-NADPH oxidase axis mediates protein radical formation and kupffer cell activation in carbon tetrachloride-mediated steatohepatitis in obese mice. Free Radic. Biol. Med. 52, 1666–1679 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  117. Dunning, S. et al. Superoxide anions and hydrogen peroxide inhibit proliferation of activated rat stellate cells and induce different modes of cell death. Liver Int. 29, 922–932 (2009).

    Article  PubMed  CAS  Google Scholar 

  118. Zhan, S. S. et al. Phagocytosis of apoptotic bodies by hepatic stellate cells induces NADPH oxidase and is associated with liver fibrosis in vivo. Hepatology 43, 435–443 (2006).

    Article  PubMed  CAS  Google Scholar 

  119. Leung, T. M. & Nieto, N. CYP2E1 and oxidant stress in alcoholic and non-alcoholic fatty liver disease. J. Hepatol. 58, 395–398 (2013).

    Article  PubMed  CAS  Google Scholar 

  120. Choi, S. & Diehl, A. M. Role of inflammation in nonalcoholic steatohepatitis. Curr. Opin. Gastroenterol. 21, 702–707 (2005).

    Article  PubMed  Google Scholar 

  121. Chung, H. K. et al. The indole derivative NecroX-7 improves nonalcoholic steatohepatitis in ob/ob mice through suppression of mitochondrial ROS/RNS and inflammation. Liver Int. 35, 1341–1353 (2015).

    Article  PubMed  CAS  Google Scholar 

  122. Wree, A., Broderick, L., Canbay, A., Hoffman, H. M. & Feldstein, A. E. From NAFLD to NASH to cirrhosis-new insights into disease mechanisms. Nat. Rev. Gastroenterol. Hepatol. 10, 627–636 (2013).

    Article  PubMed  CAS  Google Scholar 

  123. Yamaguchi, K. et al. Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis. Hepatology 45, 1366–1374 (2007).

    Article  PubMed  CAS  Google Scholar 

  124. Li, Z. Z., Berk, M., McIntyre, T. M. & Feldstein, A. E. Hepatic lipid partitioning and liver damage in nonalcoholic fatty liver disease: role of stearoyl-CoA desaturase. J. Biol. Chem. 284, 5637–5644 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. Monetti, M. et al. Dissociation of hepatic steatosis and insulin resistance in mice overexpressing DGAT in the liver. Cell Metab. 6, 69–78 (2007).

    Article  PubMed  CAS  Google Scholar 

  126. 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).

    Article  PubMed  CAS  Google Scholar 

  127. Cynis, H. et al. Inhibition of glutaminyl cyclases alleviates CCL2-mediated inflammation of non-alcoholic fatty liver disease in mice. Int. J. Exp. Pathol. 94, 217–225 (2013).

    PubMed  PubMed Central  CAS  Google Scholar 

  128. Da Silva Morais, A. et al. Prevention of steatohepatitis by pioglitazone: implication of adiponectin-dependent inhibition of SREBP-1c and inflammation. J. Hepatol. 50, 489–500 (2009).

    Article  PubMed  CAS  Google Scholar 

  129. Das, S. et al. NADPH oxidase-derived peroxynitrite drives inflammation in mice and human nonalcoholic steatohepatitis via TLR4-lipid raft recruitment. Am. J. Pathol. 185, 1944–1957 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  130. Chen, H. L. et al. Kefir peptides prevent high-fructose corn syrup-induced non-alcoholic fatty liver disease in a murine model by modulation of inflammation and the JAK2 signaling pathway. Nutr. Diabetes 6, e237 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  131. Han, M. S. et al. Lysophosphatidylcholine as a death effector in the lipoapoptosis of hepatocytes. J. Lipid Res. 49, 84–97 (2008).

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  133. Kakazu, E., Mauer, A. S., Yin, M. & Malhi, H. Hepatocytes release ceramide-enriched pro-inflammatory extracellular vesicles in an IRE1alpha-dependent manner. J. Lipid Res. 57, 233–245 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  134. Cazanave, S. C. et al. Death receptor 5 signaling promotes hepatocyte lipoapoptosis. J. Biol. Chem. 286, 39336–39348 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  135. 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).

    Article  PubMed  CAS  Google Scholar 

  136. Mari, M. et al. Mitochondrial free cholesterol loading sensitizes to TNF- and Fas-mediated steatohepatitis. Cell Metab. 4, 185–198 (2006).

    Article  PubMed  CAS  Google Scholar 

  137. Andreozzi, P. et al. [Predictors of liver fibrosis in patients with non-alcoholic fatty liver disease. The role of metabolic syndrome, insulin-resistance and inflammation]. Recenti Prog. Med. 103, 570–574 (2012).

    PubMed  Google Scholar 

  138. Ioannou, G. N. et al. Cholesterol crystallization within hepatocyte lipid droplets and its role in murine NASH. J. Lipid Res. 58, 1067–1079 (2017).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  139. Rajamaki, K. et al. Cholesterol crystals activate the NLRP3 inflammasome in human macrophages: a novel link between cholesterol metabolism and inflammation. PLOS ONE 5, e11765 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  140. Wree, A. et al. NLRP3 inflammasome driven liver injury and fibrosis: roles of IL- 17 and TNF in mice. Hepatology https://doi.org/10.1002/hep.29523 (2017).

    Article  PubMed  Google Scholar 

  141. Gan, L. T. et al. Hepatocyte free cholesterol lipotoxicity results from JNK1-mediated mitochondrial injury and is HMGB1 and TLR4-dependent. J. Hepatol. 61, 1376–1384 (2014).

    Article  PubMed  CAS  Google Scholar 

  142. Foroughi, M. et al. Relationship between non-alcoholic fatty liver disease and inflammation in patients with non-alcoholic fatty liver. Adv. Biomed. Res. 5, 28 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  143. Fujii, H. & Kawada, N. Inflammation and fibrogenesis in steatohepatitis. J. Gastroenterol. 47, 215–225 (2012).

    Article  PubMed  CAS  Google Scholar 

  144. Perez-Carreras, M. et al. Defective hepatic mitochondrial respiratory chain in patients with nonalcoholic steatohepatitis. Hepatology 38, 999–1007 (2003).

    Article  PubMed  CAS  Google Scholar 

  145. Rolo, A. P., Teodoro, J. S. & Palmeira, C. M. Role of oxidative stress in the pathogenesis of nonalcoholic steatohepatitis. Free Radic. Biol. Med. 52, 59–69 (2012).

    Article  PubMed  CAS  Google Scholar 

  146. Shimada, K. et al. Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity 36, 401–414 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  147. Carlos, D. et al. Mitochondrial DNA activates the NLRP3 inflammasome and predisposes to type 1 diabetes in murine model. Front. Immunol. 8, 164 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  148. Luedde, T., Kaplowitz, N. & Schwabe, R. F. Cell death and cell death responses in liver disease: mechanisms and clinical relevance. Gastroenterology 147, 765–783.e4 (2014).

    Article  PubMed  CAS  Google Scholar 

  149. Hirsova, P. & Gores, G. J. Death receptor-mediated cell death and proinflammatory signaling in nonalcoholic steatohepatitis. Cell. Mol. Gastroenterol. Hepatol. 1, 17–27 (2015).

    Article  PubMed  Google Scholar 

  150. Iredale, J. P. et al. Mechanisms of spontaneous resolution of rat liver fibrosis. Hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors. J. Clin. Invest. 102, 538–549 (1998).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  151. Wree, A., Mehal, W. Z. & Feldstein, A. E. Targeting cell death and sterile inflammation loop for the treatment of nonalcoholic steatohepatitis. Semin. Liver Dis. 36, 27–36 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  152. Feldstein, A. E. et al. Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis. Gastroenterology 125, 437–443 (2003).

    Article  PubMed  Google Scholar 

  153. Wang, P. X. et al. Targeting CASP8 and FADD-like apoptosis regulator ameliorates nonalcoholic steatohepatitis in mice and nonhuman primates. Nat. Med. 23, 439–449 (2017).

    Article  PubMed  CAS  Google Scholar 

  154. Feldstein, A. E. et al. Free fatty acids promote hepatic lipotoxicity by stimulating TNF-alpha expression via a lysosomal pathway. Hepatology 40, 185–194 (2004).

    Article  PubMed  CAS  Google Scholar 

  155. Hirsova, P., Ibrahim, S. H., Gores, G. J. & Malhi, H. Lipotoxic lethal and sublethal stress signaling in hepatocytes: relevance to NASH pathogenesis. J. Lipid Res. 57, 1758–1770 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  156. Canbay, A. et al. Apoptotic body engulfment by a human stellate cell line is profibrogenic. Lab. Invest. 83, 655–663 (2003).

    Article  PubMed  CAS  Google Scholar 

  157. Watanabe, A. et al. Apoptotic hepatocyte DNA inhibits hepatic stellate cell chemotaxis via toll-like receptor 9. Hepatology 46, 1509–1518 (2007).

    Article  PubMed  CAS  Google Scholar 

  158. Hirsova, P. et al. TRAIL deletion prevents liver inflammation but not adipose tissue inflammation during murine diet-induced obesity. Hepatol. Commun. 1, 648–662 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  159. Idrissova, L. et al. TRAIL receptor deletion in mice suppresses the inflammation of nutrient excess. J. Hepatol. 62, 1156–1163 (2015).

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  161. Xiang, M. et al. Targeting hepatic TRAF1-ASK1 signaling to improve inflammation, insulin resistance, and hepatic steatosis. J. Hepatol. 64, 1365–1377 (2016).

    Article  PubMed  CAS  Google Scholar 

  162. Ha, H., Han, D. & Choi, Y. TRAF-mediated TNFR-family signaling. Curr. Protoc. Immunol. https://doi.org/10.1002/0471142735.im1109ds87 (2009).

  163. Zhang, P. et al. The deubiquitinating enzyme TNFAIP3 mediates inactivation of hepatic ASK1 and ameliorates nonalcoholic steatohepatitis. Nat. Med. 24, 84–94 (2018).

    Article  PubMed  CAS  Google Scholar 

  164. Machado, M. V. et al. Reduced lipoapoptosis, hedgehog pathway activation and fibrosis in caspase-2 deficient mice with non-alcoholic steatohepatitis. Gut 64, 1148–1157 (2015).

    Article  PubMed  CAS  Google Scholar 

  165. Johnson, E. S. et al. Metabolomic profiling reveals a role for caspase-2 in lipoapoptosis. J. Biol. Chem. 288, 14463–14475 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  166. Machado, M. V. et al. Caspase-2 promotes obesity, the metabolic syndrome and nonalcoholic fatty liver disease. Cell Death Dis. 7, e2096 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  167. Linkermann, A. & Green, D. R. Necroptosis. N. Engl. J. Med. 370, 455–465 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  168. Dara, L., Liu, Z.-X. & Kaplowitz, N. Questions and controversies: the role of necroptosis in liver disease. Cell Death Discov. 2, 16089 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  169. Afonso, M. B. et al. Necroptosis is a key pathogenic event in human and experimental murine models of non-alcoholic steatohepatitis. Clin. Sci. 129, 721–739 (2015).

    Article  CAS  Google Scholar 

  170. Gautheron, J. et al. A positive feedback loop between RIP3 and JNK controls non-alcoholic steatohepatitis. EMBO Mol. Med. 6, 1062–1074 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  171. Hatting, M. et al. Hepatocyte caspase-8 is an essential modulator of steatohepatitis in rodents. Hepatology 57, 2189–2201 (2013).

    Article  PubMed  CAS  Google Scholar 

  172. Wang, Z., Jiang, H., Chen, S., Du, F. & Wang, X. The mitochondrial phosphatase PGAM5 functions at the convergence point of multiple necrotic death pathways. Cell 148, 228–243 (2012).

    Article  PubMed  CAS  Google Scholar 

  173. Vince, J. E. et al. Inhibitor of apoptosis proteins limit RIP3 kinase-dependent interleukin-1 activation. Immunity 36, 215–227 (2012).

    Article  PubMed  CAS  Google Scholar 

  174. Cookson, B. T. & Brennan, M. A. Pro-inflammatory programmed cell death. Trends Microbiol. 9, 113–114 (2001).

    Article  PubMed  CAS  Google Scholar 

  175. Alegre, F., Pelegrin, P. & Feldstein, A. E. Inflammasomes in liver fibrosis. Semin. Liver Dis. 37, 119–127 (2017).

    Article  PubMed  CAS  Google Scholar 

  176. Jo, E. K., Kim, J. K., Shin, D. M. & Sasakawa, C. Molecular mechanisms regulating NLRP3 inflammasome activation. Cell. Mol. Immunol. 13, 148–159 (2016).

    Article  PubMed  CAS  Google Scholar 

  177. Liu, X. et al. Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature 535, 153 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  178. Wree, A. et al. NLRP3 inflammasome activation results in hepatocyte pyroptosis, liver inflammation, and fibrosis in mice. Hepatology 59, 898–910 (2014).

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  181. Baroja-Mazo, A. et al. The NLRP3 inflammasome is released as a particulate danger signal that amplifies the inflammatory response. Nat. Immunol. 15, 738–748 (2014).

    Article  PubMed  CAS  Google Scholar 

  182. Franklin, B. S. et al. The adaptor ASC has extracellular and ‘prionoid’ activities that propagate inflammation. Nat. Immunol. 15, 727–737 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  184. Yang, L., Li, P., Fu, S., Calay, E. S. & Hotamisligil, G. S. Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance. Cell Metab. 11, 467–478 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  185. Singh, R. et al. Autophagy regulates lipid metabolism. Nature 458, 1131–1135 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  186. Amir, M. & Czaja, M. J. Autophagy in nonalcoholic steatohepatitis. Expert Rev. Gastroenterol. Hepatol. 5, 159–166 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  187. Kwanten, W. J. et al. Hepatocellular autophagy modulates the unfolded protein response and fasting-induced steatosis in mice. Am J. Physiol. Gastrointest. Liver Physiol. 311, G599–G609 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  188. Lemasters, J. J. Selective mitochondrial autophagy, or mitophagy, as a targeted defense against oxidative stress, mitochondrial dysfunction, and aging. Rejuvenation Res. 8, 3–5 (2005).

    Article  PubMed  CAS  Google Scholar 

  189. Wagner, M., Zollner, G. & Trauner, M. Nuclear receptors in liver disease. Hepatology 53, 1023–1034 (2011).

    Article  PubMed  CAS  Google Scholar 

  190. Schmitz, G. & Ecker, J. The opposing effects of n-3 and n-6 fatty acids. Prog. Lipid Res. 47, 147–155 (2008).

    Article  PubMed  CAS  Google Scholar 

  191. Larter, C. Z. et al. Activation of peroxisome proliferator-activated receptor alpha by dietary fish oil attenuates steatosis, but does not prevent experimental steatohepatitis because of hepatic lipoperoxide accumulation. J. Gastroenterol. Hepatol. 23, 267–275 (2008).

    Article  PubMed  CAS  Google Scholar 

  192. Shan, W. et al. Peroxisome proliferator-activated receptor-beta/delta protects against chemically induced liver toxicity in mice. Hepatology 47, 225–235 (2008).

    Article  PubMed  CAS  Google Scholar 

  193. Bouhlel, M. A. et al. PPARgamma activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties. Cell Metab. 6, 137–143 (2007).

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  195. Griffett, K. et al. The LXR inverse agonist SR9238 suppresses fibrosis in a model of non-alcoholic steatohepatitis. Mol. Metab. 4, 353–357 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  196. Cave, M. C. et al. Nuclear receptors and nonalcoholic fatty liver disease. Biochim. Biophys. Acta 1859, 1083–1099 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  197. Tanaka, N., Aoyama, T., Kimura, S. & Gonzalez, F. J. Targeting nuclear receptors for the treatment of fatty liver disease. Pharmacol. Ther. 179, 142–157 (2017).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  198. Meex, R. C. R. & Watt, M. J. Hepatokines: linking nonalcoholic fatty liver disease and insulin resistance. Nat. Rev. Endocrinol. 13, 509–520 (2017).

    Article  PubMed  CAS  Google Scholar 

  199. Lai, K. K., Kolippakkam, D. & Beretta, L. Comprehensive and quantitative proteome profiling of the mouse liver and plasma. Hepatology 47, 1043–1051 (2008).

    Article  PubMed  CAS  Google Scholar 

  200. Joshi-Barve, S. et al. Palmitic acid induces production of proinflammatory cytokine interleukin-8 from hepatocytes. Hepatology 46, 823–830 (2007).

    Article  PubMed  CAS  Google Scholar 

  201. Meex, R. C. et al. Fetuin B is a secreted hepatocyte factor linking steatosis to impaired glucose metabolism. Cell Metab. 22, 1078–1089 (2015).

    Article  PubMed  CAS  Google Scholar 

  202. 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).

    Article  PubMed  CAS  Google Scholar 

  203. Jung, T. W., Yoo, H. J. & Choi, K. M. Implication of hepatokines in metabolic disorders and cardiovascular diseases. BBA Clin. 5, 108–113 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  204. Lebensztejn, D. M., Flisiak-Jackiewicz, M., Bialokoz-Kalinowska, I., Bobrus-Chociej, A. & Kowalska, I. Hepatokines and non-alcoholic fatty liver disease. Acta Biochim. Pol. 63, 459–467 (2016).

    Article  PubMed  CAS  Google Scholar 

  205. Lotze, M. T. et al. The grateful dead: damage-associated molecular pattern molecules and reduction/oxidation regulate immunity. Immunol. Rev. 220, 60–81 (2007).

    Article  PubMed  CAS  Google Scholar 

  206. Arrese, M., Cabrera, D., Kalergis, A. M. & Feldstein, A. E. Innate Immunity and Inflammation in NAFLD/NASH. Dig. Dis. Sci. 61, 1294–1303 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  207. Kesar, V. & Odin, J. A. Toll-like receptors and liver disease. Liver Int. 34, 184–196 (2014).

    Article  PubMed  CAS  Google Scholar 

  208. Bieghs, V. & Trautwein, C. Innate immune signaling and gut-liver interactions in non-alcoholic fatty liver disease. Hepatobiliary Surg. Nutr. 3, 377–385 (2014).

    PubMed  PubMed Central  Google Scholar 

  209. Takeuchi, O. & Akira, S. Pattern recognition receptors and inflammation. Cell 140, 805–820 (2010).

    Article  PubMed  CAS  Google Scholar 

  210. 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).

    Article  PubMed  CAS  Google Scholar 

  211. Cai, C. et al. NLRP3 deletion inhibits the non-alcoholic steatohepatitis development and inflammation in kupffer cells induced by palmitic acid. Inflammation 40, 1875–1883 (2017).

    Article  PubMed  CAS  Google Scholar 

  212. Watanabe, A. et al. Inflammasome-mediated regulation of hepatic stellate cells. Am. J. Physiol. Gastrointest. Liver Physiol. 296, G1248–G1257 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  213. Krenkel, O. & Tacke, F. Macrophages in nonalcoholic fatty liver disease: a role model of pathogenic immunometabolism. Semin. Liver Dis. 37, 189–197 (2017).

    Article  PubMed  CAS  Google Scholar 

  214. 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).

    Article  PubMed  CAS  Google Scholar 

  215. Reid, D. T. et al. Kupffer cells undergo fundamental changes during the development of experimental NASH and are critical in initiating liver damage and inflammation. PLOS ONE 11, e0159524 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  216. 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-alpha production. J. Biol. Chem. 287, 40161–40172 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  217. Soehnlein, O., Steffens, S., Hidalgo, A. & Weber, C. Neutrophils as protagonists and targets in chronic inflammation. Nat. Rev. Immunol. 17, 248–261 (2017).

    Article  PubMed  CAS  Google Scholar 

  218. Xu, R., Huang, H., Zhang, Z. & Wang, F. S. The role of neutrophils in the development of liver diseases. Cell. Mol. Immunol. 11, 224–231 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  219. Rensen, S. S. et al. Neutrophil-derived myeloperoxidase aggravates non-alcoholic steatohepatitis in low-density lipoprotein receptor-deficient mice. PLOS ONE 7, e52411 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  220. Ibusuki, R. et al. Transgenic expression of human neutrophil peptide-1 enhances hepatic fibrosis in mice fed a choline-deficient, L-amino acid-defined diet. Liver Int. 33, 1549–1556 (2013).

    PubMed  CAS  Google Scholar 

  221. Alkhouri, N. et al. Neutrophil to lymphocyte ratio: a new marker for predicting steatohepatitis and fibrosis in patients with nonalcoholic fatty liver disease. Liver Int. 32, 297–302 (2012).

    Article  PubMed  CAS  Google Scholar 

  222. Anstee, Q. M., Seth, D. & Day, C. P. Genetic factors that affect risk of alcoholic and nonalcoholic fatty liver disease. Gastroenterology 150, 1728–1744.e7 (2016).

    Article  PubMed  Google Scholar 

  223. Dongiovanni, P. et al. PNPLA3 I148M polymorphism and progressive liver disease. World J. Gastroenterol. 19, 6969–6978 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  224. Romeo, S. et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 40, 1461–1465 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  225. Li, J. Z. et al. Chronic overexpression of PNPLA3I148M in mouse liver causes hepatic steatosis. J. Clin. Invest. 122, 4130–4144 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  226. BasuRay, S., Smagris, E., Cohen, J. C. & Hobbs, H. H. The PNPLA3 variant associated with fatty liver disease (I148M) accumulates on lipid droplets by evading ubiquitylation. Hepatology 66, 1111–1124 (2017).

    Article  PubMed  CAS  Google Scholar 

  227. Bruschi, F. V. et al. The PNPLA3 I148M variant modulates the fibrogenic phenotype of human hepatic stellate cells. Hepatology 65, 1875–1890 (2017).

    Article  PubMed  CAS  Google Scholar 

  228. Mancina, R. M. et al. The MBOAT7-TMC4 variant rs641738 increases risk of nonalcoholic fatty liver disease in individuals of European descent. Gastroenterology 150, 1219–1230.e6 (2016).

    Article  PubMed  CAS  Google Scholar 

  229. Sookoian, S. et al. Mitochondrial genome architecture in non-alcoholic fatty liver disease. J. Pathol. 240, 437–449 (2016).

    Article  PubMed  CAS  Google Scholar 

  230. Lee, J., Kim, Y., Friso, S. & Choi, S. W. Epigenetics in non-alcoholic fatty liver disease. Mol. Aspects Med. 54, 78–88 (2017).

    Article  PubMed  CAS  Google Scholar 

  231. Pirola, C. J. et al. Epigenetic modification of liver mitochondrial DNA is associated with histological severity of nonalcoholic fatty liver disease. Gut 62, 1356–1363 (2013).

    Article  PubMed  CAS  Google Scholar 

  232. Murphy, S. K. et al. Relationship between methylome and transcriptome in patients with nonalcoholic fatty liver disease. Gastroenterology 145, 1076–1087 (2013).

    Article  PubMed  CAS  Google Scholar 

  233. Celikbilek, M. et al. Circulating microRNAs in patients with non-alcoholic fatty liver disease. World J. Hepatol. 6, 613–620 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  234. Fernandez-Hernando, C., Suarez, Y., Rayner, K. J. & Moore, K. J. MicroRNAs in lipid metabolism. Curr. Opin. Lipidol. 22, 86–92 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  235. Gori, M., Arciello, M. & Balsano, C. MicroRNAs in nonalcoholic fatty liver disease: novel biomarkers and prognostic tools during the transition from steatosis to hepatocarcinoma. Biomed. Res. Int. 2014, 741465 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  236. Tryndyak, V. P. Plasma microRNAs are sensitive indicators of inter-strain differences in the severity of liver injury induced in mice by a choline- and folate-deficient diet. Toxicol Appl Pharmacol. 262, 52–59 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  237. Cortez, M. A. et al. MicroRNAs in body fluids — the mix of hormones and biomarkers. Nat. Rev. Clin. Oncol. 8, 467–477 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  238. Fullerton, J. N. & Gilroy, D. W. Resolution of inflammation: a new therapeutic frontier. Nat. Rev. Drug Discov. 15, 551–567 (2016).

    Article  PubMed  CAS  Google Scholar 

  239. Rius, B. et al. The specialized pro-resolving lipid mediator maresin 1 protects hepatocytes from lipotoxic and hypoxia-induced endoplasmic reticulum stress. FASEB J 31, 5384–5398 (2017).

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  241. Li, P., He, K., Li, J., Liu, Z. & Gong, J. The role of Kupffer cells in hepatic diseases. Mol. Immunol. 85, 222–229 (2017).

    Article  PubMed  CAS  Google Scholar 

  242. Alisi, A. et al. The role of tissue macrophage-mediated inflammation on NAFLD pathogenesis and its clinical implications. Mediators Inflamm. 2017, 8162421 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  243. Serhan, C. N. Treating inflammation and infection in the 21st century: new hints from decoding resolution mediators and mechanisms. FASEB J. 31, 1273–1288 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  244. Lopez-Vicario, C. et al. Molecular interplay between delta5/delta6 desaturases and long-chain fatty acids in the pathogenesis of non-alcoholic steatohepatitis. Gut 63, 344–355 (2014).

    Article  PubMed  CAS  Google Scholar 

  245. Araya, J. et al. Decreased liver fatty acid delta-6 and delta-5 desaturase activity in obese patients. Obes 18, 1460–1463 (2010).

    Article  CAS  Google Scholar 

  246. Rius, B. et al. Resolvin D1 primes the resolution process initiated by calorie restriction in obesity-induced steatohepatitis. FASEB J. 28, 836–848 (2014).

    Article  PubMed  CAS  Google Scholar 

  247. Borgeson, E. et al. Lipoxin A4 attenuates adipose inflammation. FASEB J. 26, 4287–4294 (2012).

    Article  PubMed  CAS  Google Scholar 

  248. Martinez-Fernandez, L. et al. Maresin 1 improves insulin sensitivity and attenuates adipose tissue inflammation in ob/ob and diet-induced obese mice. FASEB J. 31, 2135–2145 (2017).

    Article  PubMed  CAS  Google Scholar 

  249. Hotta, K. et al. Association of the rs738409 polymorphism in PNPLA3 with liver damage and the development of nonalcoholic fatty liver disease. BMC Med. Genet. 11, 172 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  250. Petta, S. et al. IL28B and PNPLA3 polymorphisms affect histological liver damage in patients with non-alcoholic fatty liver disease. J. Hepatol. 56, 1356–1362 (2012).

    Article  PubMed  CAS  Google Scholar 

  251. Rotman, Y., Koh, C., Zmuda, J. M., Kleiner, D. E. & Liang, T. J. The association of genetic variability in patatin-like phospholipase domain-containing protein 3 (PNPLA3) with histological severity of nonalcoholic fatty liver disease. Hepatology 52, 894–903 (2010).

    Article  PubMed  CAS  Google Scholar 

  252. Dongiovanni, P. et al. Transmembrane 6 superfamily member 2 gene variant disentangles nonalcoholic steatohepatitis from cardiovascular disease. Hepatology 61, 506–514 (2015).

    Article  PubMed  CAS  Google Scholar 

  253. Kozlitina, J. et al. Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 46, 352–356 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  254. Liu, Y. L. et al. TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease. Nat. Commun. 5, 4309 (2014).

    Article  PubMed  CAS  Google Scholar 

  255. Petta, S. et al. Glucokinase regulatory protein gene polymorphism affects liver fibrosis in non-alcoholic fatty liver disease. PLOS ONE 9, e87523 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  256. Santoro, N. et al. Variant in the glucokinase regulatory protein (GCKR) gene is associated with fatty liver in obese children and adolescents. Hepatology 55, 781–789 (2012).

    Article  PubMed  CAS  Google Scholar 

  257. Cefalu, A. B. et al. A novel APOB mutation identified by exome sequencing cosegregates with steatosis, liver cancer, and hypocholesterolemia. Arterioscler Thromb. Vasc. Biol. 33, 2021–2025 (2013).

    Article  PubMed  CAS  Google Scholar 

  258. Di Filippo, M. et al. Homozygous MTTP and APOB mutations may lead to hepatic steatosis and fibrosis despite metabolic differences in congenital hypocholesterolemia. J. Hepatol. 61, 891–902 (2014).

    Article  PubMed  CAS  Google Scholar 

  259. Nobili, V. et al. A 4-polymorphism risk score predicts steatohepatitis in children with nonalcoholic fatty liver disease. J. Pediatr. Gastroenterol. Nutr. 58, 632–636 (2014).

    Article  PubMed  CAS  Google Scholar 

  260. Valenti, L. et al. LPIN1 rs13412852 polymorphism in pediatric nonalcoholic fatty liver disease. J. Pediatr. Gastroenterol. Nutr. 54, 588–593 (2012).

    CAS  Google Scholar 

  261. Fares, R. et al. The UCP2 -866 G>A promoter region polymorphism is associated with nonalcoholic steatohepatitis. Liver Int. 35, 1574–1580 (2015).

    Article  PubMed  CAS  Google Scholar 

  262. Chalasani, N. et al. Genome-wide association study identifies variants associated with histologic features of nonalcoholic fatty liver disease. Gastroenterology 139, 1567–1576 (2010).

    Article  PubMed  Google Scholar 

  263. Bernard, S. et al. Association between microsomal triglyceride transfer protein gene polymorphism and the biological features of liver steatosis in patients with type II diabetes. Diabetologia 43, 995–999 (2000).

    Article  PubMed  CAS  Google Scholar 

  264. Oliveira, C. P. et al. Association of polymorphisms of glutamate-cystein ligase and microsomal triglyceride transfer protein genes in non-alcoholic fatty liver disease. J. Gastroenterol. Hepatol. 25, 357–361 (2010).

    Article  PubMed  CAS  Google Scholar 

  265. Chen, Y. et al. Hepatocyte-specific Gclc deletion leads to rapid onset of steatosis with mitochondrial injury and liver failure. Hepatology 45, 1118–1128 (2007).

    Article  PubMed  CAS  Google Scholar 

  266. Petta, S. et al. Interferon lambda 4 rs368234815 TT> δG variant is associated with liver damage in patients with nonalcoholic fatty liver disease. Hepatology 66, 1885–1893 (2017).

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

The work of the authors was supported by the US National Institutes of Health (R01 DK113592-01,1U01AA024206-01 TO A.E.F.), the German Research Foundation (SCHU3146/1-2 to S.S.) and the Chilean government through the Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT 1150327 to M.A. and 11171001 to D.C.) and the Comisión Nacional de Investigación Científica y Tecnológica (grant CONICYT PIA/Basal PFB12, Basal Centre for Excellence in Science and Technology to M.A.).

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Authors and Affiliations

  1. Department of Pediatrics, University of California, San Diego, CA, USA

    Susanne Schuster & Ariel E. Feldstein

  2. Department of Gastroenterology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile

    Daniel Cabrera & Marco Arrese

  3. Departamento de Ciencias Químicas y Biológicas, Facultad de Salud, Universidad Bernardo O Higgins, Santiago, Chile

    Daniel Cabrera

  4. Centre for Aging and Regeneration (CARE), Department of Cellular and Molecular Biology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile

    Marco Arrese

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  4. Ariel E. Feldstein
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Contributions

All authors researched data for the article. S.S., M.A. and A.E.F. contributed substantially to the discussion of content. S.S., D.C. and M.A. wrote the manuscript, and all authors reviewed and edited the manuscript before submission.

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Correspondence to Ariel E. Feldstein.

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Glossary

Hepatocyte ballooning

A histomorphological change observed in hepatocytes during cell death, usually defined on tissue stained with haematoxylin and eosin as a cellular enlargement in normal hepatocyte diameter of 1.5–2 times with rarefied cytoplasm.

Lipotoxicity

The toxic effects of excessive free fatty acids (FFAs) leading to cellular injury and death caused by FFAs themselves or by their metabolites.

Sterile cell death

Cell death induced by activation of a sterile inflammatory response via interactions with immune cells that can result in a full inflammatory response in the absence of an infection.

Gut–liver axis

Physiological crosstalk between the liver and gut that consists of a myriad of signals with both immunological and metabolic effects in each organ.

Leaky gut

Leakage that occurs as a result of damage to the intestinal lining, which makes the internal environment of the gut leak out of the intestines into the bloodstream, triggering an immune response.

Fenton reaction

A reaction in which iron acts as a catalyst and reacts with hydrogen peroxide to generate highly reactive hydroxyl radicals.

Unfolded protein response

(UPR). A response that is activated by an accumulation of misfolded and/or unfolded proteins in the endoplasmic reticulum. The unfolded protein response aims to restore normal cellular function by inhibiting translation, degrading misfolded proteins and activating signalling pathways that increase the production of molecular chaperones that participate in protein folding.

Free cholesterol

A measure of cholesterol that has not been esterified.

Intestinal dysbiosis

A state in which there are perturbations of the composition of gut commensal communities.

Autacoids

Physiologically active factors that are produced by the body and typically act near the site of synthesis for a brief duration.

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Schuster, S., Cabrera, D., Arrese, M. et al. Triggering and resolution of inflammation in NASH. Nat Rev Gastroenterol Hepatol 15, 349–364 (2018). https://doi.org/10.1038/s41575-018-0009-6

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