Review Article | Published:

Apoptosis and necroptosis in the liver: a matter of life and death

Nature Reviews Gastroenterology & Hepatology (2018) | Download Citation

Abstract

Cell death represents a basic biological paradigm that governs outcomes and long-term sequelae in almost every hepatic disease condition. Acute liver failure is characterized by massive loss of parenchymal cells but is usually followed by restitution ad integrum. By contrast, cell death in chronic liver diseases often occurs at a lesser extent but leads to long-term alterations in organ architecture and function, contributing to chronic hepatocyte turnover, the recruitment of immune cells and activation of hepatic stellate cells. These chronic cell death responses contribute to the development of liver fibrosis, cirrhosis and cancer. It has become evident that, besides apoptosis, necroptosis is a highly relevant form of programmed cell death in the liver. Differential activation of specific forms of programmed cell death might not only affect outcomes in liver diseases but also offer novel opportunities for therapeutic intervention. Here, we summarize the underlying molecular mechanisms and open questions about disease-specific activation and roles of programmed cell death forms, their contribution to response signatures and their detection. We focus on the role of apoptosis and necroptosis in acute liver injury, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH) and liver cancer, and possible translations into clinical applications.

Key points

  • Cell death is a fundamental driver of liver disease progression to liver fibrosis, cirrhosis and hepatocellular carcinoma.

  • Depending on the underlying disease entity, distinct forms of programmed cell death and cell death response pathways can be activated in the liver.

  • Necroptosis is a new form of programmed cell death that is activated by the necrosome, which consists of the kinases receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and RIPK3 and the pseudokinase mixed lineage kinase domain-like protein (MLKL).

  • Despite necroptosis being challenging to detect in vivo, there is accumulating evidence that this cell death form is a pathogenically relevant driver in several liver diseases that were associated with apoptosis.

  • Necroptosis seems to be particularly important in nonalcoholic fatty liver disease, nonalcoholic steatohepatitis and liver cancer but does not contribute to acetaminophen toxicity or ischaemia–reperfusion injury.

  • A better functional characterization of necroptosis in liver disease models might lead to novel therapeutic strategies that target necroptosis to prevent the progression and decompensation of chronic liver disease.

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References

  1. 1.

    Michalopoulos, G. K. & DeFrances, M. Liver regeneration. Adv. Biochem. Eng. Biotechnol. 93, 101–134 (2005).

  2. 2.

    Benedetti, A., Jezequel, A. M. & Orlandi, F. Preferential distribution of apoptotic bodies in acinar zone 3 of normal human and rat liver. J. Hepatol. 7, 319–324 (1988).

  3. 3.

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

  4. 4.

    Villanueva, A. & Luedde, T. The transition from inflammation to cancer in the liver. Clin. Liver Dis. 8, 89–93 (2016).

  5. 5.

    Schuppan, D. & Afdhal, N. H. Liver cirrhosis. Lancet 371, 838–851 (2008).

  6. 6.

    Wallach, D., Kang, T. B., Dillon, C. P. & Green, D. R. Programmed necrosis in inflammation: toward identification of the effector molecules. Science https://doi.org/10.1126/science.aaf2154 (2016).

  7. 7.

    Yuan, J., Najafov, A. & Py, B. F. Roles of caspases in necrotic cell death. Cell 167, 1693–1704 (2016).

  8. 8.

    Stockwell, B. R. et al. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell 171, 273–285 (2017).

  9. 9.

    Vande Walle, L. & Lamkanfi, M. Pyroptosis. Curr. Biol. 26, R568–R572 (2016).

  10. 10.

    Fuchs, Y. & Steller, H. Programmed cell death in animal development and disease. Cell 147, 742–758 (2011).

  11. 11.

    Galluzzi, L., Lopez-Soto, A., Kumar, S. & Kroemer, G. Caspases connect cell-death signaling to organismal homeostasis. Immunity 44, 221–231 (2016).

  12. 12.

    Fan, Y. & Bergmann, A. Apoptosis-induced compensatory proliferation. The cell is dead. long live the cell! Trends Cell Biol. 18, 467–473 (2008).

  13. 13.

    Jorgensen, I., Rayamajhi, M. & Miao, E. A. Programmed cell death as a defence against infection. Nat. Rev. Immunol. 17, 151–164 (2017).

  14. 14.

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

  15. 15.

    Louandre, C. et al. The retinoblastoma (Rb) protein regulates ferroptosis induced by sorafenib in human hepatocellular carcinoma cells. Cancer Lett. 356, 971–977 (2015).

  16. 16.

    Wang, H. et al. Characterization of ferroptosis in murine models of hemochromatosis. Hepatology 66, 449–465 (2017).

  17. 17.

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

  18. 18.

    Bialik, S. & Kimchi, A. Lethal weapons: DAP-kinase, autophagy and cell death: DAP-kinase regulates autophagy. Curr. Opin. Cell Biol. 22, 199–205 (2010).

  19. 19.

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

  20. 20.

    Angeli, J. P. F., Shah, R., Pratt, D. A. & Conrad, M. Ferroptosis inhibition: mechanisms and opportunities. Trends Pharmacol. Sci. 38, 489–498 (2017).

  21. 21.

    Majno, G. & Joris, I. Apoptosis, oncosis, and necrosis. An overview of cell death. Am. J. Pathol. 146, 3–15 (1995).

  22. 22.

    Van Cruchten, S. & Van Den Broeck, W. Morphological and biochemical aspects of apoptosis, oncosis and necrosis. Anat. Histol. Embryol. 31, 214–223 (2002).

  23. 23.

    Malhi, H., Gores, G. J. & Lemasters, J. J. Apoptosis and necrosis in the liver: a tale of two deaths? Hepatology 43, S31–S44 (2006).

  24. 24.

    Davidovich, P., Kearney, C. J. & Martin, S. J. Inflammatory outcomes of apoptosis, necrosis and necroptosis. Biol. Chem. 395, 1163–1171 (2014).

  25. 25.

    McIlwain, D. R., Berger, T. & Mak, T. W. Caspase functions in cell death and disease. Cold Spring Harb Perspect Biol 5, https://doi.org/10.1101/cshperspect.a008656 (2013).

  26. 26.

    Liedtke, C. & Trautwein, C. The role of TNF and Fas dependent signaling in animal models of inflammatory liver injury and liver cancer. Eur. J. Cell Biol. 91, 582–589 (2012).

  27. 27.

    Schwabe, R. F. & Brenner, D. A. Mechanisms of Liver Injury. I. TNF-alpha-induced liver injury: role of IKK, JNK, and ROS pathways. Am. J. Physiol. Gastrointest. Liver Physiol. 290, G583–G589 (2006).

  28. 28.

    Dondelinger, Y., Darding, M., Bertrand, M. J. & Walczak, H. Poly-ubiquitination in TNFR1-mediated necroptosis. Cell. Mol. Life Sci. 73, 2165–2176 (2016).

  29. 29.

    Bettermann, K. et al. TAK1 suppresses a NEMO-dependent but NF-kappaB-independent pathway to liver cancer. Cancer Cell 17, 481–496 (2010).

  30. 30.

    Vucur, M. et al. RIP3 inhibits inflammatory hepatocarcinogenesis but promotes cholestasis by controlling caspase-8- and JNK-dependent compensatory cell proliferation. Cell Rep. 4, 776–790 (2013).

  31. 31.

    Luedde, T. et al. Deletion of NEMO/IKKgamma in liver parenchymal cells causes steatohepatitis and hepatocellular carcinoma. Cancer Cell 11, 119–132 (2007).

  32. 32.

    Kondylis, V. et al. NEMO prevents steatohepatitis and hepatocellular carcinoma by inhibiting RIPK1 kinase activity-mediated hepatocyte apoptosis. Cancer Cell 28, 582–598 (2015).

  33. 33.

    Luedde, T. et al. IKK1 and IKK2 cooperate to maintain bile duct integrity in the liver. Proc. Natl Acad. Sci. USA 105, 9733–9738 (2008).

  34. 34.

    Yin, X. M. & Ding, W. X. Death receptor activation-induced hepatocyte apoptosis and liver injury. Curr. Mol. Med. 3, 491–508 (2003).

  35. 35.

    Guicciardi, M. E., Malhi, H., Mott, J. L. & Gores, G. J. Apoptosis and necrosis in the liver. Compr. Physiol. 3, 977–1010 (2013).

  36. 36.

    Koppe, C. et al. IkappaB kinasealpha/beta control biliary homeostasis and hepatocarcinogenesis in mice by phosphorylating the cell-death mediator receptor-interacting protein kinase 1. Hepatology 64, 1217–1231 (2016).

  37. 37.

    Schneider, A. T. et al. RIPK1 Suppresses a TRAF2-dependent pathway to liver cancer. Cancer Cell 31, 94–109 (2017).

  38. 38.

    Vucur, M., Schneider, A. T., Gautheron, J. & Luedde, T. The enigma of RIPK1 in the liver: more than just a kinase. Mol. Cell Oncol. 4, e1304191 (2017).

  39. 39.

    Laster, S. M., Wood, J. G. & Gooding, L. R. Tumor necrosis factor can induce both apoptic and necrotic forms of cell lysis. J. Immunol. 141, 2629–2634 (1988).

  40. 40.

    Vercammen, D. et al. Inhibition of caspases increases the sensitivity of L929 cells to necrosis mediated by tumor necrosis factor. J. Exp. Med. 187, 1477–1485 (1998).

  41. 41.

    Holler, N. et al. Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nat. Immunol. 1, 489–495 (2000).

  42. 42.

    Degterev, A. et al. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat. Chem. Biol. 1, 112–119 (2005).

  43. 43.

    Zhang, D. W. et al. RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science 325, 332–336 (2009).

  44. 44.

    He, S. et al. Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha. Cell 137, 1100–1111 (2009).

  45. 45.

    Cho, Y. S. et al. Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell 137, 1112–1123 (2009).

  46. 46.

    Sun, L. et al. Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell 148, 213–227 (2012).

  47. 47.

    Gong, Y. N., Guy, C., Crawford, J. C. & Green, D. R. Biological events and molecular signaling following MLKL activation during necroptosis. Cell Cycle 16, 1748–1760 (2017).

  48. 48.

    Newton, K. et al. Activity of protein kinase RIPK3 determines whether cells die by necroptosis or apoptosis. Science 343, 1357–1360 (2014).

  49. 49.

    Tummers, B. & Green, D. R. Caspase-8: regulating life and death. Immunol. Rev. 277, 76–89 (2017).

  50. 50.

    Ravichandran, K. S. Beginnings of a good apoptotic meal: the find-me and eat-me signaling pathways. Immunity 35, 445–455 (2011).

  51. 51.

    Martin, S. J., Henry, C. M. & Cullen, S. P. A perspective on mammalian caspases as positive and negative regulators of inflammation. Mol. Cell 46, 387–397 (2012).

  52. 52.

    Bosurgi, L., Hughes, L. D., Rothlin, C. V. & Ghosh, S. Death begets a new beginning. Immunol. Rev. 280, 8–25 (2017).

  53. 53.

    Kaczmarek, A., Vandenabeele, P. & Krysko, D. V. Necroptosis: the release of damage-associated molecular patterns and its physiological relevance. Immunity 38, 209–223 (2013).

  54. 54.

    Kumar, S., Calianese, D. & Birge, R. B. Efferocytosis of dying cells differentially modulate immunological outcomes in tumor microenvironment. Immunol. Rev. 280, 149–164 (2017).

  55. 55.

    Lemasters, J. J. Dying a thousand deaths: redundant pathways from different organelles to apoptosis and necrosis. Gastroenterology 129, 351–360 (2005).

  56. 56.

    Matzinger, P. The danger model: a renewed sense of self. Science 296, 301–305 (2002).

  57. 57.

    Kang, T. B., Yang, S. H., Toth, B., Kovalenko, A. & Wallach, D. Caspase-8 blocks kinase RIPK3-mediated activation of the NLRP3 inflammasome. Immunity 38, 27–40 (2013).

  58. 58.

    Lawlor, K. E. et al. RIPK3 promotes cell death and NLRP3 inflammasome activation in the absence of MLKL. Nat. Commun. 6, 6282 (2015).

  59. 59.

    Moriwaki, K., Bertin, J., Gough, P. J. & Chan, F. K. A. RIPK3-caspase 8 complex mediates atypical pro-IL-1beta processing. J. Immunol. 194, 1938–1944 (2015).

  60. 60.

    Seki, E. & Schwabe, R. F. Hepatic inflammation and fibrosis: functional links and key pathways. Hepatology 61, 1066–1079 (2015).

  61. 61.

    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).

  62. 62.

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

  63. 63.

    Affo, S., Yu, L. X. & Schwabe, R. F. The role of cancer-associated fibroblasts and fibrosis in liver cancer. Annu. Rev. Pathol. 12, 153–186 (2017).

  64. 64.

    Sun, B. & Karin, M. Inflammation and liver tumorigenesis. Front. Med. 7, 242–254 (2013).

  65. 65.

    Michalopoulos, G. K. & DeFrances, M. C. Liver regeneration. Science 276, 60–66 (1997).

  66. 66.

    Schaub, J. R., Malato, Y., Gormond, C. & Willenbring, H. Evidence against a stem cell origin of new hepatocytes in a common mouse model of chronic liver injury. Cell Rep. 8, 933–939 (2014).

  67. 67.

    Malato, Y. et al. Fate tracing of mature hepatocytes in mouse liver homeostasis and regeneration. J. Clin. Invest. 121, 4850–4860 (2011).

  68. 68.

    Yanger, K. et al. Adult hepatocytes are generated by self-duplication rather than stem cell differentiation. Cell Stem Cell 15, 340–349 (2014).

  69. 69.

    Sharpless, N. E. & DePinho, R. A. How stem cells age and why this makes us grow old. Nat. Rev. Mol. Cell Biol. 8, 703–713 (2007).

  70. 70.

    Morrison, S. J. & Kimble, J. Asymmetric and symmetric stem-cell divisions in development and cancer. Nature 441, 1068–1074 (2006).

  71. 71.

    Boege, Y. et al. A dual role of Caspase-8 in triggering and sensing proliferation-associated DNA damage, a key determinant of liver cancer development. Cancer Cell 32, 342–359 (2017).

  72. 72.

    Galluzzi, L., Buque, A., Kepp, O., Zitvogel, L. & Kroemer, G. Immunological effects of conventional chemotherapy and targeted anticancer agents. Cancer Cell 28, 690–714 (2015).

  73. 73.

    Garg, A. D. & Agostinis, P. Cell death and immunity in cancer: from danger signals to mimicry of pathogen defense responses. Immunol. Rev. 280, 126–148 (2017).

  74. 74.

    Krysko, O. et al. Necroptotic cell death in anti-cancer therapy. Immunol. Rev. 280, 207–219 (2017).

  75. 75.

    Beutler, B. Neo-ligands for innate immune receptors and the etiology of sterile inflammatory disease. Immunol. Rev. 220, 113–128 (2007).

  76. 76.

    Weerasinghe, S. V., Park, M. J., Portney, D. A. & Omary, M. B. Mouse genetic background contributes to hepatocyte susceptibility to Fas-mediated apoptosis. Mol. Biol. Cell 27, 3005–3012 (2016).

  77. 77.

    Bai, L. & Wang, S. Targeting apoptosis pathways for new cancer therapeutics. Annu. Rev. Med. 65, 139–155 (2014).

  78. 78.

    Hernandez, C. et al. HMGB1 links chronic liver injury to progenitor responses and hepatocarcinogenesis. J. Clin. Invest. 128, 2436–2451 (2018).

  79. 79.

    Huebener, P. et al. The HMGB1/RAGE axis triggers neutrophil-mediated injury amplification following necrosis. J. Clin. Invest. 125, 539–550 (2015).

  80. 80.

    Scaffidi, P., Misteli, T. & Bianchi, M. E. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 418, 191–195 (2002).

  81. 81.

    Arriazu, E. et al. Signalling via the osteopontin and high mobility group box-1 axis drives the fibrogenic response to liver injury. Gut 66, 1123–1137 (2017).

  82. 82.

    Khambu, B. et al. HMGB1 promotes ductular reaction and tumorigenesis in autophagy-deficient livers. J. Clin. Invest. 128, 2419–2435 (2018).

  83. 83.

    McDonald, B. et al. Intravascular danger signals guide neutrophils to sites of sterile inflammation. Science 330, 362–366 (2010).

  84. 84.

    Savio, L. E. B. et al. CD39 limits P2X7 receptor inflammatory signaling and attenuates sepsis-induced liver injury. J. Hepatol. 67, 716–726 (2017).

  85. 85.

    Hoque, R. et al. P2X7 receptor-mediated purinergic signaling promotes liver injury in acetaminophen hepatotoxicity in mice. Am. J. Physiol. Gastrointest. Liver Physiol. 302, G1171–G1179 (2012).

  86. 86.

    Kataoka, H., Kono, H., Patel, Z., Kimura, Y. & Rock, K. L. Evaluation of the contribution of multiple DAMPs and DAMP receptors in cell death-induced sterile inflammatory responses. PLOS One 9, e104741 (2014).

  87. 87.

    Marques, P. E. et al. Chemokines and mitochondrial products activate neutrophils to amplify organ injury during mouse acute liver failure. Hepatology 56, 1971–1982 (2012).

  88. 88.

    Liu, M. et al. Formylpeptide receptors are critical for rapid neutrophil mobilization in host defense against Listeria monocytogenes. Sci. Rep. 2, 786 (2012).

  89. 89.

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

  90. 90.

    Luthi, A. U. et al. Suppression of interleukin-33 bioactivity through proteolysis by apoptotic caspases. Immunity 31, 84–98 (2009).

  91. 91.

    Cayrol, C. & Girard, J. P. The IL-1-like cytokine IL-33 is inactivated after maturation by caspase-1. Proc. Natl Acad. Sci. USA 106, 9021–9026 (2009).

  92. 92.

    Rickard, J. A. et al. RIPK1 regulates RIPK3-MLKL-driven systemic inflammation and emergency hematopoiesis. Cell 157, 1175–1188 (2014).

  93. 93.

    Rankin, A. L. et al. IL-33 induces IL-13-dependent cutaneous fibrosis. J. Immunol. 184, 1526–1535 (2010).

  94. 94.

    Vannella, K. M. et al. Combinatorial targeting of TSLP, IL-25, and IL-33 in type 2 cytokine-driven inflammation and fibrosis. Sci Transl Med 8, 337ra65 (2016).

  95. 95.

    McHedlidze, T. et al. Interleukin-33-dependent innate lymphoid cells mediate hepatic fibrosis. Immunity 39, 357–371 (2013).

  96. 96.

    Tan, Z. et al. Tan, Z. et al. Interleukin-33 drives hepatic fibrosis through activation of hepatic stellate cells. Cell. Mol. Immunol. 15, 388–398 (2017).

  97. 97.

    Vasseur, P. et al. Endogenous IL-33 has no effect on the progression of fibrosis during experimental steatohepatitis. Oncotarget 8, 48563–48574 (2017).

  98. 98.

    Shi, Y., Evans, J. E. & Rock, K. L. Molecular identification of a danger signal that alerts the immune system to dying cells. Nature 425, 516–521 (2003).

  99. 99.

    Martinon, F., Petrilli, V., Mayor, A., Tardivel, A. & Tschopp, J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440, 237–241 (2006).

  100. 100.

    Watanabe, A. et al. Inflammasome-mediated regulation of hepatic stellate cells. Am. J. Physiol. Gastrointest. Liver Physiol. 296, G1248–1257 (2009).

  101. 101.

    Labat-Moleur, F. et al. TUNEL apoptotic cell detection in tissue sections: critical evaluation and improvement. J. Histochem. Cytochem. 46, 327–334 (1998).

  102. 102.

    Wieckowska, A. et al. In vivo assessment of liver cell apoptosis as a novel biomarker of disease severity in nonalcoholic fatty liver disease. Hepatology 44, 27–33 (2006).

  103. 103.

    Tamimi, T. I. et al. An apoptosis panel for nonalcoholic steatohepatitis diagnosis. J. Hepatol. 54, 1224–1229 (2011).

  104. 104.

    Mazzolini, G., Sowa, J. P. & Canbay, A. Cell death mechanisms in human chronic liver diseases: a far cry from clinical applicability. Clin. Sci. 130, 2121–2138 (2016).

  105. 105.

    Wang, H. et al. Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption upon phosphorylation by RIP3. Mol. Cell 54, 133–146 (2014).

  106. 106.

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

  107. 107.

    Roychowdhury, S., McMullen, M. R., Pisano, S. G., Liu, X. & Nagy, L. E. Absence of receptor interacting protein kinase 3 prevents ethanol-induced liver injury. Hepatology 57, 1773–1783 (2013).

  108. 108.

    Gong, Y. N. et al. ESCRT-III acts downstream of MLKL to regulate necroptotic cell death and its consequences. Cell 169, 286–300 (2017).

  109. 109.

    Yoon, S., Kovalenko, A., Bogdanov, K. & Wallach, D. MLKL, the protein that mediates necroptosis, also regulates endosomal trafficking and extracellular vesicle generation. Immunity 47, 51–65 (2017).

  110. 110.

    Panayotova-Dimitrova, D. et al. cFLIP regulates skin homeostasis and protects against TNF-induced keratinocyte apoptosis. Cell Rep. 5, 397–408 (2013).

  111. 111.

    Strilic, B. et al. Tumour-cell-induced endothelial cell necroptosis via death receptor 6 promotes metastasis. Nature 536, 215–218 (2016).

  112. 112.

    de Graaf, I. A. et al. Preparation and incubation of precision-cut liver and intestinal slices for application in drug metabolism and toxicity studies. Nat. Protoc. 5, 1540–1551 (2010).

  113. 113.

    Vasilikos, L., Spilgies, L. M., Knop, J. & Wong, W. W. Regulating the balance between necroptosis, apoptosis and inflammation by inhibitors of apoptosis proteins. Immunol. Cell Biol. 95, 160–165 (2017).

  114. 114.

    Wu, Y. T. et al. zVAD-induced necroptosis in L929 cells depends on autocrine production of TNFalpha mediated by the PKC-MAPKs-AP-1 pathway. Cell Death Differ. 18, 26–37 (2011).

  115. 115.

    Krenkel, O., Mossanen, J. C. & Tacke, F. Immune mechanisms in acetaminophen-induced acute liver failure. Hepatobiliary Surg. Nutr. 3, 331–343 (2014).

  116. 116.

    Schneider, A. T., Gautheron, J., Tacke, F., Vucur, M. & Luedde, T. Receptor interacting protein kinase 1 (RIPK1) in hepatocytes does not mediate murine acetaminophen toxicity. Hepatology 64, 306–308 (2016).

  117. 117.

    Takemoto, K. et al. Necrostatin-1 protects against reactive oxygen species (ROS)-induced hepatotoxicity in acetaminophen-induced acute liver failure. FEBS Open Bio 4, 777–787 (2014).

  118. 118.

    Dara, L. et al. Receptor interacting protein kinase 1 mediates murine acetaminophen toxicity independent of the necrosome and not through necroptosis. Hepatology 62, 1847–1857 (2015).

  119. 119.

    Deutsch, M. et al. Divergent effects of RIP1 or RIP3 blockade in murine models of acute liver injury. Cell Death Dis. 6, e1759 (2015).

  120. 120.

    Li, J. X. et al. The B-Raf(V600E) inhibitor dabrafenib selectively inhibits RIP3 and alleviates acetaminophen-induced liver injury. Cell Death Dis. 5, e1278 (2014).

  121. 121.

    Ramachandran, A. et al. Receptor interacting protein kinase 3 is a critical early mediator of acetaminophen-induced hepatocyte necrosis in mice. Hepatology 58, 2099–2108 (2013).

  122. 122.

    Takahashi, N. et al. Necrostatin-1 analogues: critical issues on the specificity, activity and in vivo use in experimental disease models. Cell Death Dis. 3, e437 (2012).

  123. 123.

    Wang, K. Molecular mechanisms of liver injury: apoptosis or necrosis. Exp. Toxicol. Pathol. 66, 351–356 (2014).

  124. 124.

    Friedmann Angeli, J. P. et al. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat. Cell Biol. 16, 1180–1191 (2014).

  125. 125.

    Khan, H. A., Ahmad, M. Z., Khan, J. A. & Arshad, M. I. Crosstalk of liver immune cells and cell death mechanisms in different murine models of liver injury and its clinical relevance. Hepatobiliary Pancreat. Dis. Int. 16, 245–256 (2017).

  126. 126.

    Gunther, C. et al. The pseudokinase MLKL mediates programmed hepatocellular necrosis independently of RIPK3 during hepatitis. J. Clin. Invest. 126, 4346–4360 (2016).

  127. 127.

    Filliol, A. et al. RIPK1 protects from TNF-alpha-mediated liver damage during hepatitis. Cell Death Dis. 7, e2462 (2016).

  128. 128.

    Herrmann, O. et al. IKK mediates ischemia-induced neuronal death. Nat. Med. 11, 1322–1329 (2005).

  129. 129.

    Linkermann, A. et al. Necroptosis in immunity and ischemia-reperfusion injury. Am. J. Transplant 13, 2797–2804 (2013).

  130. 130.

    Luedde, M. et al. RIP3, a kinase promoting necroptotic cell death, mediates adverse remodelling after myocardial infarction. Cardiovasc. Res. 103, 206–216 (2014).

  131. 131.

    Singh, S., Osna, N. A. & Kharbanda, K. K. Treatment options for alcoholic and non-alcoholic fatty liver disease: a review. World J. Gastroenterol. 23, 6549–6570 (2017).

  132. 132.

    Tsochatzis, E. A. & Newsome, P. N. Non-alcoholic fatty liver disease and the interface between primary and secondary care. Lancet Gastroenterol. Hepatol. 3, 509–517 (2018).

  133. 133.

    Cobbina, E. & Akhlaghi, F. Non-alcoholic fatty liver disease (NAFLD) - pathogenesis, classification, and effect on drug metabolizing enzymes and transporters. Drug Metab. Rev. 49, 197–211 (2017).

  134. 134.

    Diehl, A. M. & Day, C. Cause, pathogenesis, and treatment of nonalcoholic steatohepatitis. N. Engl. J. Med. 377, 2063–2072 (2017).

  135. 135.

    Day, C. P. & James, O. F. Steatohepatitis: a tale of two “hits”? Gastroenterology 114, 842–845 (1998).

  136. 136.

    Buzzetti, E., Pinzani, M. & Tsochatzis, E. A. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metabolism 65, 1038–1048 (2016).

  137. 137.

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

  138. 138.

    Thapaliya, S. et al. Caspase 3 inactivation protects against hepatic cell death and ameliorates fibrogenesis in a diet-induced NASH model. Dig. Dis. Sci. 59, 1197–1206 (2014).

  139. 139.

    Alkhouri, N., Carter-Kent, C. & Feldstein, A. E. Apoptosis in nonalcoholic fatty liver disease: diagnostic and therapeutic implications. Expert Rev. Gastroenterol. Hepatol. 5, 201–212 (2011).

  140. 140.

    Witek, R. P. et al. Pan-caspase inhibitor VX-166 reduces fibrosis in an animal model of nonalcoholic steatohepatitis. Hepatology 50, 1421–1430 (2009).

  141. 141.

    Ratziu, V. et al. A phase 2, randomized, double-blind, placebo-controlled study of GS-9450 in subjects with nonalcoholic steatohepatitis. Hepatology 55, 419–428 (2012).

  142. 142.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02960204?term=NCT02960204&rank=1 (2018).

  143. 143.

    Malhi, H. & Gores, G. J. Molecular mechanisms of lipotoxicity in nonalcoholic fatty liver disease. Semin. Liver Dis. 28, 360–369 (2008).

  144. 144.

    Volkmann, X. et al. Caspase activation is associated with spontaneous recovery from acute liver failure. Hepatology 47, 1624–1633 (2008).

  145. 145.

    Kaiser, W. J. et al. RIP3 mediates the embryonic lethality of caspase-8-deficient mice. Nature 471, 368–372 (2011).

  146. 146.

    Gautheron, J. et al. The necroptosis-inducing kinase RIPK3 dampens adipose tissue inflammation and glucose intolerance. Nat. Commun. 7, 11869 (2016).

  147. 147.

    Malhi, H., Bronk, S. F., Werneburg, N. W. & Gores, G. J. Free fatty acids induce JNK-dependent hepatocyte lipoapoptosis. J. Biol. Chem. 281, 12093–12101 (2006).

  148. 148.

    Zhang, W. et al. Tumor necrosis factor-alpha accelerates apoptosis of steatotic hepatocytes from a murine model of non-alcoholic fatty liver disease. Biochem. Biophys. Res. Commun. 391, 1731–1736 (2010).

  149. 149.

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

  150. 150.

    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).

  151. 151.

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

  152. 152.

    Nakagawa, H. et al. ER stress cooperates with hypernutrition to trigger TNF-dependent spontaneous HCC development. Cancer Cell 26, 331–343 (2014).

  153. 153.

    Wang, X. et al. Hepatocyte TAZ/WWTR1 promotes inflammation and fibrosis in nonalcoholic steatohepatitis. Cell Metab. 24, 848–862 (2016).

  154. 154.

    Sanyal, A. J. et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N. Engl. J. Med. 362, 1675–1685 (2010).

  155. 155.

    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).

  156. 156.

    Benvegnu, L., Gios, M., Boccato, S. & Alberti, A. Natural history of compensated viral cirrhosis: a prospective study on the incidence and hierarchy of major complications. Gut 53, 744–749 (2004).

  157. 157.

    Wen, C. P. et al. Hepatocellular carcinoma risk prediction model for the general population: the predictive power of transaminases. J. Natl Cancer Inst. 104, 1599–1611 (2012).

  158. 158.

    Yang, H. I. et al. Risk estimation for hepatocellular carcinoma in chronic hepatitis B (REACH-B): development and validation of a predictive score. Lancet Oncol. 12, 568–574 (2011).

  159. 159.

    Hassan, M., Watari, H., AbuAlmaaty, A., Ohba, Y. & Sakuragi, N. Apoptosis and molecular targeting therapy in cancer. Biomed. Res. Int. 2014, 150845 (2014).

  160. 160.

    Wahl, K. et al. Increased apoptosis induction in hepatocellular carcinoma by a novel tumor-targeted TRAIL fusion protein combined with bortezomib. Hepatology 57, 625–636 (2013).

  161. 161.

    Koo, G. B. et al. Methylation-dependent loss of RIP3 expression in cancer represses programmed necrosis in response to chemotherapeutics. Cell Res. 25, 707–725 (2015).

  162. 162.

    Deng, G. L., Zeng, S. & Shen, H. Chemotherapy and target therapy for hepatocellular carcinoma: new advances and challenges. World J. Hepatol. 7, 787–798 (2015).

  163. 163.

    Linton, S. D. et al. First-in-class pan caspase inhibitor developed for the treatment of liver disease. J. Med. Chem. 48, 6779–6782 (2005).

  164. 164.

    Valentino, K. L., Gutierrez, M., Sanchez, R., Winship, M. J. & Shapiro, D. A. First clinical trial of a novel caspase inhibitor: anti-apoptotic caspase inhibitor, IDN-6556, improves liver enzymes. Int. J. Clin. Pharmacol. Ther. 41, 441–449 (2003).

  165. 165.

    Baskin-Bey, E. S. et al. Clinical trial of the pan-caspase inhibitor, IDN-6556, in human liver preservation injury. Am. J. Transplant 7, 218–225 (2007).

  166. 166.

    Pockros, P. J. et al. Oral IDN-6556, an antiapoptotic caspase inhibitor, may lower aminotransferase activity in patients with chronic hepatitis C. Hepatology 46, 324–329 (2007).

  167. 167.

    Shiffman, M. L. et al. Clinical trial: the efficacy and safety of oral PF-03491390, a pancaspase inhibitor - a randomized placebo-controlled study in patients with chronic hepatitis C. Aliment. Pharmacol. Ther. 31, 969–978 (2010).

  168. 168.

    Szabo, G. & Petrasek, J. Inflammasome activation and function in liver disease. Nat. Rev. Gastroenterol. Hepatol. 12, 387–400 (2015).

  169. 169.

    Lee, F. A. et al. Randomized phase II study of the X-linked Inhibitor of Apoptosis (XIAP) antisense AEG35156 in combination with sorafenib in patients with advanced Hepatocellular Carcinoma (HCC). Am. J. Clin. Oncol. 39, 609–613 (2016).

  170. 170.

    Kopalli, S. R., Kang, T. B. & Koppula, S. Necroptosis inhibitors as therapeutic targets in inflammation mediated disorders - a review of the current literature and patents. Expert Opin. Ther. Pat. 26, 1239–1256 (2016).

  171. 171.

    Li, D. et al. Natural product kongensin A is a non-canonical HSP90 inhibitor that blocks RIP3-dependent necroptosis. Cell Chem. Biol. 23, 257–266 (2016).

  172. 172.

    Dai, M. C. et al. Curcumin protects against iron induced neurotoxicity in primary cortical neurons by attenuating necroptosis. Neurosci. Lett. 536, 41–46 (2013).

  173. 173.

    Conrad, M., Angeli, J. P., Vandenabeele, P. & Stockwell, B. R. Regulated necrosis: disease relevance and therapeutic opportunities. Nat. Rev. Drug Discov. 15, 348–366 (2016).

  174. 174.

    Gujral, J. S., Knight, T. R., Farhood, A., Bajt, M. L. & Jaeschke, H. Mode of cell death after acetaminophen overdose in mice: apoptosis or oncotic necrosis? Toxicol. Sci. 67, 322–328 (2002).

  175. 175.

    Masuichi, H. et al. Significant role of apoptosis in type-1 autoimmune hepatitis. Osaka City Med. J. 45, 61–79 (1999).

  176. 176.

    Fox, C. K., Furtwaengler, A., Nepomuceno, R. R., Martinez, O. M. & Krams, S. M. Apoptotic pathways in primary biliary cirrhosis and autoimmune hepatitis. Liver 21, 272–279 (2001).

  177. 177.

    Kuo, P. C. et al. Apoptosis and hepatic allograft reperfusion injury. Clin. Transplant 12, 219–223 (1998).

  178. 178.

    Gautheron, J., Vucur, M. & Luedde, T. Necroptosis in nonalcoholic steatohepatitis. Cell. Mol. Gastroenterol. Hepatol. 1, 264–265 (2015).

  179. 179.

    Davidson, D. G. & Eastham, W. N. Acute liver necrosis following overdose of paracetamol. Br. Med. J. 2, 497–499 (1966).

  180. 180.

    Tzimas, G. N. et al. Correlation of cell necrosis and tissue calcification with ischemia/reperfusion injury after liver transplantation. Transplant Proc. 36, 1766–1768 (2004).

  181. 181.

    Jaeschke, H., Cover, C. & Bajt, M. L. Role of caspases in acetaminophen-induced liver injury. Life Sci. 78, 1670–1676 (2006).

  182. 182.

    Anstee, Q. M. et al. Impact of pan-caspase inhibition in animal models of established steatosis and non-alcoholic steatohepatitis. J. Hepatol. 53, 542–550 (2010).

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Acknowledgements

The authors thank A. T. Schneider for her support in designing figures and M. Vucur for critically reading the manuscript. Work in the laboratory of R.F.S. was supported by US NIH grants 5R01CA200597, 5R01CA190844, 1R01DK116620 and 5U01AA021912. Work in the laboratory of T.L. was supported by a Mildred-Scheel Endowed Professorship from the German Cancer Aid (Deutsche Krebshilfe), the German Research Foundation (DFG) (LU 1360/3-1 and SFB-TRR57/P06), the Interdisciplinary Centre for Clinical Research (IZKF) Aachen-Germany and the Ernst-Jung Foundation Hamburg.

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Nature Reviews Gastroenterology & Hepatology thanks M. Conrad and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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  1. Department of Medicine, Columbia University, New York, NY, USA

    • Robert F. Schwabe
  2. Institute of Human Nutrition, Columbia University, New York, NY, USA

    • Robert F. Schwabe
  3. Department of Medicine III, Division of Gastroenterology, Hepatology and Hepatobiliary Oncology, University Hospital Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen, Aachen, Germany

    • Tom Luedde

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Both authors contributed equally to the manuscript.

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https://doi.org/10.1038/s41575-018-0065-y