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  • Review Article
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Cellular stress in the pathogenesis of nonalcoholic steatohepatitis and liver fibrosis

Abstract

The burden of chronic liver disease is rising substantially worldwide. Fibrosis, characterized by excessive deposition of extracellular matrix proteins, is the common pathway leading to cirrhosis, and limited treatment options are available. There is increasing evidence suggesting the role of cellular stress responses contributing to fibrogenesis. This Review provides an overview of studies that analyse the role of cellular stress in different cell types involved in fibrogenesis, including hepatocytes, hepatic stellate cells, liver sinusoidal endothelial cells and macrophages.

Key points

  • Chronic activation of endoplasmic reticulum stress in hepatocytes drives nonalcoholic steatohepatitis (ΝASH) pathogenesis, insulin resistance, fat accumulation, inflammation, fibrogenesis and liver fibrosis through inadequate unfolded protein response, cell death and inflammation.

  • Mitochondrial dysfunction and oxidative stress drive NASH and liver fibrosis by causing hepatocyte damage, immune cell activation and inflammation.

  • Cellular stress pathways in hepatocytes also contribute to fibrogenesis independent of NASH.

  • Intracellular reactive oxygen species generation provokes endoplasmic reticulum stress and autophagy that contribute to the activation of hepatic stellate cells.

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Fig. 1: Overview of cell types in hepatic fibrosis.
Fig. 2: Overview of oxidative stress-activated pathways in NASH.
Fig. 3: Overview of cellular stress in hepatic stellate cells.
Fig. 4: Small molecules targeting each UPR branch.

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References

  1. Cheemerla, S. & Balakrishnan, M. Global epidemiology of chronic liver disease. Clin. Liver Dis. 17, 365–370 (2021).

    Article  Google Scholar 

  2. Rinella, M. E. et al. A multi-society Delphi consensus statement on new fatty liver disease nomenclature. Hepatology https://doi.org/10.1097/HEP.0000000000000520 (2023).

    Article  PubMed  Google Scholar 

  3. Kisseleva, T. & Brenner, D. Molecular and cellular mechanisms of liver fibrosis and its regression. Nat. Rev. Gastroenterol. Hepatol. 18, 151–166 (2021).

    Article  PubMed  Google Scholar 

  4. Lu, M. et al. Serum biomarkers indicate long-term reduction in liver fibrosis in patients with sustained virological response to treatment for HCV infection. Clin. Gastroenterol. Hepatol. 14, 1044–1055.e3 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Iwaisako, K. et al. Origin of myofibroblasts in the fibrotic liver in mice. Proc. Natl Acad. Sci. USA 111, E3297–E3305 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Friedman, S. L. Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol. Rev. 88, 125–172 (2008).

    Article  CAS  PubMed  Google Scholar 

  7. Ramachandran, P. et al. Resolving the fibrotic niche of human liver cirrhosis at single-cell level. Nature 575, 512–518 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  9. Baiceanu, A., Mesdom, P., Lagouge, M. & Foufelle, F. Endoplasmic reticulum proteostasis in hepatic steatosis. Nat. Rev. Endocrinol. 12, 710–722 (2016).

    Article  CAS  PubMed  Google Scholar 

  10. Lebeaupin, C. et al. Endoplasmic reticulum stress signalling and the pathogenesis of non-alcoholic fatty liver disease. J. Hepatol. 69, 927–947 (2018).

    Article  CAS  PubMed  Google Scholar 

  11. Wang, M. & Kaufman, R. J. Protein misfolding in the endoplasmic reticulum as a conduit to human disease. Nature 529, 326–335 (2016).

    Article  CAS  PubMed  Google Scholar 

  12. Hetz, C., Chevet, E. & Oakes, S. A. Proteostasis control by the unfolded protein response. Nat. Cell Biol. 17, 829–838 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Shore, G. C., Papa, F. R. & Oakes, S. A. Signaling cell death from the endoplasmic reticulum stress response. Curr. Opin. Cell Biol. 23, 143–149 (2011).

    Article  CAS  PubMed  Google Scholar 

  14. Calfon, M. et al. IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature 415, 92–96 (2002).

    Article  CAS  PubMed  Google Scholar 

  15. Vattem, K. M. & Wek, R. C. Reinitiation involving upstream ORFs regulates ATF4 mRNA translation in mammalian cells. Proc. Natl Acad. Sci. USA 101, 11269–11274 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Zhang, T. et al. Gp78, an E3 ubiquitin ligase acts as a gatekeeper suppressing nonalcoholic steatohepatitis (NASH) and liver cancer. PLoS ONE 10, e0118448 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Cullinan, S. B. et al. Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival. Mol. Cell. Biol. 23, 7198–7209 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Tirosh, B., Iwakoshi, N. N., Glimcher, L. H. & Ploegh, H. L. Rapid turnover of unspliced xbp-1 as a factor that modulates the unfolded protein response. J. Biol. Chem. 281, 5852–5860 (2006).

    Article  CAS  PubMed  Google Scholar 

  19. Jurkin, J. et al. The mammalian tRNA ligase complex mediates splicing of XBP1 mRNA and controls antibody secretion in plasma cells. EMBO J. 33, 2922–2936 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Haze, K., Yoshida, H., Yanagi, H., Yura, T. & Mori, K. Mammalian transcription factor atf6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. Mol. Biol. Cell 10, 3787–3799 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Shen, J., Chen, X., Hendershot, L. & Prywes, R. ER stress regulation of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking of golgi localization signals. Dev. Cell 3, 99–111 (2002).

    Article  CAS  PubMed  Google Scholar 

  22. Yoshida, H. et al. ATF6 activated by proteolysis binds in the presence of NF-Y (CBF) directly to the cis-acting element responsible for the mammalian unfolded protein response. Mol. Cell Biol. 20, 6755–6767 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Duwaerts, C. C. & Maiers, J. L. ER disposal pathways in chronic liver disease: protective, pathogenic, and potential therapeutic targets. Front. Mol. Biosci. 8, 804097 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Ajoolabady, A. et al. Endoplasmic reticulum stress in liver diseases. Hepatology 77, 619–639 (2022).

    Article  PubMed  Google Scholar 

  25. Han, J. & Kaufman, R. J. The role of ER stress in lipid metabolism and lipotoxicity. J. Lipid Res. 57, 1329–1338 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Pagliassotti, M. J. Endoplasmic reticulum stress in nonalcoholic fatty liver disease. Annu. Rev. Nutr. 32, 17–33 (2012).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Pfaffenbach, K. T. et al. Linking endoplasmic reticulum stress to cell death in hepatocytes: roles of C/EBP homologous protein and chemical chaperones in palmitate-mediated cell death. Am. J. Physiol. Endocrinol. Metab. 298, E1027–E1035 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Duwaerts, C. C. et al. Hepatocyte-specific deletion of XBP1 sensitizes mice to liver injury through hyperactivation of IRE1α. Cell Death Differ. 28, 1455–1465 (2021).

    Article  CAS  PubMed  Google Scholar 

  30. Lake, A. D. et al. The adaptive endoplasmic reticulum stress response to lipotoxicity in progressive human nonalcoholic fatty liver disease. Toxicol. Sci. 137, 26–35 (2014).

    Article  CAS  PubMed  Google Scholar 

  31. Puri, P. et al. Activation and dysregulation of the unfolded protein response in nonalcoholic fatty liver disease. Gastroenterology 134, 568–576 (2008).

    Article  CAS  PubMed  Google Scholar 

  32. González-Rodríguez, A. et al. Impaired autophagic flux is associated with increased endoplasmic reticulum stress during the development of NAFLD. Cell Death Dis. 5, e1179 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Lebeaupin, C. et al. ER stress induces NLRP3 inflammasome activation and hepatocyte death. Cell Death Dis. 6, e1879 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Lebeaupin, C. et al. Bax inhibitor-1 protects from nonalcoholic steatohepatitis by limiting inositol-requiring enzyme 1 alpha signaling in mice. Hepatology 68, 515–532 (2018).

    Article  CAS  PubMed  Google Scholar 

  35. Bailly-Maitre, B. et al. Hepatic bax inhibitor-1 inhibits IRE1α and protects from obesity-associated insulin resistance and glucose intolerance. J. Biol. Chem. 285, 6198–6207 (2010).

    Article  CAS  PubMed  Google Scholar 

  36. Sanyal, A. J. et al. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology 120, 1183–1192 (2001).

    Article  CAS  PubMed  Google Scholar 

  37. 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  CAS  PubMed  Google Scholar 

  38. Hirsova, P., Ibrabim, 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  CAS  PubMed  PubMed Central  Google Scholar 

  39. Wang, D., Wei, Y. & Pagliassotti, M. J. Saturated fatty acids promote endoplasmic reticulum stress and liver injury in rats with hepatic steatosis. Endocrinology 147, 943–951 (2006).

    Article  CAS  PubMed  Google Scholar 

  40. Akazawa, Y. et al. Palmitoleate attenuates palmitate-induced Bim and PUMA up-regulation and hepatocyte lipoapoptosis. J. Hepatol. 52, 586–593 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  42. 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  CAS  PubMed  PubMed Central  Google Scholar 

  43. Bronner, D. N. et al. Endoplasmic reticulum stress activates the inflammasome via nlrp3- and caspase-2-driven mitochondrial damage. Immunity 43, 451–462 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Lerner, A. G. et al. IRE1α induces thioredoxin-interacting protein to activate the NLRP3 inflammasome and promote programmed cell death under irremediable ER stress. Cell Metab. 16, 250–264 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Zhang, J., Zhang, K., Li, Z. & Guo, B. ER stress-induced inflammasome activation contributes to hepatic inflammation and steatosis. J. Clin. Cell Immunol. 7, 457 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Schuster, S., Cabrera, D., Arrese, M. & Feldstein, A. E. Triggering and resolution of inflammation in NASH. Nat. Rev. Gastroenterol. Hepatol. 15, 349–364 (2018).

    Article  CAS  PubMed  Google Scholar 

  47. Kaufmann, B., Kim, A. D. & Feldstein, A. E. in Inflammasome Biology: Fundamentals, Role in Disease States, and Therapeutic Opportunities Ch. 22 (ed. Pelegrin, P.) 355–368 (Academic Press, 2023).

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

    Article  CAS  PubMed  Google Scholar 

  49. Csak, T. et al. Fatty acid and endotoxin activate inflammasomes in mouse hepatocytes that release danger signals to stimulate immune cells. Hepatology 54, 133–144 (2011).

    Article  CAS  PubMed  Google Scholar 

  50. Gaul, S. et al. Hepatocyte pyroptosis and release of inflammasome particles induce stellate cell activation and liver fibrosis. J. Hepatol. 74, 156–167 (2021).

    Article  CAS  PubMed  Google Scholar 

  51. Gan, C., Cai, Q., Tang, C. & Gao, J. Inflammasomes and pyroptosis of liver cells in liver fibrosis. Front. Immunol. 13, 896473 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Xu, B. et al. Gasdermin D plays a key role as a pyroptosis executor of non-alcoholic steatohepatitis in humans and mice. J. Hepatol. 68, 773–782 (2018).

    Article  CAS  PubMed  Google Scholar 

  53. Bhandary, B., Marahatta, A., Kim, H.-R. & Chae, H.-J. An involvement of oxidative stress in endoplasmic reticulum stress and its associated diseases. Int. J. Mol. Sci. 14, 434–456 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Koliaki, C. et al. Adaptation of hepatic mitochondrial function in humans with non-alcoholic fatty liver is lost in steatohepatitis. Cell Metab. 21, 739–746 (2015).

    Article  CAS  PubMed  Google Scholar 

  55. Fromenty, B. & Roden, M. Mitochondrial alterations in fatty liver diseases. J. Hepatol. 78, 415–429 (2022).

    Article  PubMed  Google Scholar 

  56. Fromenty, B., Robin, M. A., Igoudjil, A., Mansouri, A. & Pessayre, D. The ins and outs of mitochondrial dysfunction in NASH. Diabetes Metab. 30, 121–138 (2004).

    Article  CAS  PubMed  Google Scholar 

  57. Malhotra, J. D. & Kaufman, R. J. Endoplasmic reticulum stress and oxidative stress: a vicious cycle or a double-edged sword? Antioxid. Redox Signal. 9, 2277–2294 (2007).

    Article  CAS  PubMed  Google Scholar 

  58. Malhotra, J. D. et al. Antioxidants reduce endoplasmic reticulum stress and improve protein secretion. Proc. Natl Acad. Sci. USA 105, 18525–18530 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Mansouri, A., Gattolliat, C.-H. & Asselah, T. Mitochondrial dysfunction and signaling in chronic liver diseases. Gastroenterology 155, 629–647 (2018).

    Article  CAS  PubMed  Google Scholar 

  60. Tu, B. P. & Weissman, J. S. Oxidative protein folding in eukaryotes. J. Cell Biol. 164, 341–346 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Sevier, C. S. & Kaiser, C. A. Ero1 and redox homeostasis in the endoplasmic reticulum. Biochim. Biophys. Acta 1783, 549–556 (2008).

    Article  CAS  PubMed  Google Scholar 

  62. van der Vlies, D. et al. Oxidation of ER resident proteins upon oxidative stress: effects of altering cellular redox/antioxidant status and implications for protein maturation. Antioxid. Redox Signal. 5, 381–387 (2003).

    Article  PubMed  Google Scholar 

  63. Flamment, M., Hajduch, E., Ferré, P. & Foufelle, F. New insights into ER stress-induced insulin resistance. Trends Endocrinol. Metab. 23, 381–390 (2012).

    Article  CAS  PubMed  Google Scholar 

  64. Chowdhry, S. et al. Loss of Nrf2 markedly exacerbates nonalcoholic steatohepatitis. Free. Radic. Biol. Med. 48, 357–371 (2010).

    Article  CAS  PubMed  Google Scholar 

  65. Okada, K. et al. Nrf2 inhibits hepatic iron accumulation and counteracts oxidative stress-induced liver injury in nutritional steatohepatitis. J. Gastroenterol. 47, 924–935 (2012).

    Article  PubMed  Google Scholar 

  66. Ding, X. et al. Chicoric acid ameliorates nonalcoholic fatty liver disease via the AMPK/Nrf2/NFκB signaling pathway and restores gut microbiota in high-fat-diet-fed mice. Oxid. Med. Cell. Longev. 2020, 9734560 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  67. Qu, L.-L. et al. Gastrodin ameliorates oxidative stress and proinflammatory response in nonalcoholic fatty liver disease through the AMPK/Nrf2 pathway: antioxidative and antiinflammatory activities of gastrodin in NAFLD. Phytother. Res. 30, 402–411 (2016).

    Article  CAS  PubMed  Google Scholar 

  68. Shimozono, R. et al. Nrf2 activators attenuate the progression of nonalcoholic steatohepatitis-related fibrosis in a dietary rat model. Mol. Pharmacol. 84, 62–70 (2013).

    Article  CAS  PubMed  Google Scholar 

  69. Zhang, Y.-K. J., Yeager, R. L., Tanaka, Y. & Klaassen, C. D. Enhanced expression of Nrf2 in mice attenuates the fatty liver produced by a methionine- and choline-deficient diet. Toxicol. Appl. Pharmacol. 245, 326–334 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Begriche, K., Massart, J., Robin, M.-A., Bonnet, F. & Fromenty, B. Mitochondrial adaptations and dysfunctions in nonalcoholic fatty liver disease. Hepatology 58, 1497–1507 (2013).

    Article  CAS  PubMed  Google Scholar 

  71. Ramanathan, R., Ali, A. H. & Ibdah, J. A. Mitochondrial dysfunction plays central role in nonalcoholic fatty liver disease. Int. J. Mol. Sci. 23, 7280 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Serviddio, G., Bellanti, F., Vendemiale, G. & Altomare, E. Mitochondrial dysfunction in nonalcoholic steatohepatitis. Expert. Rev. Gastroenterol. Hepatol. 5, 233–244 (2011).

    Article  CAS  PubMed  Google Scholar 

  73. Rui, L. Energy metabolism in the liver. Compr. Physiol. 4, 177–197 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Schirrmacher, V. Mitochondria at work: new insights into regulation and dysregulation of cellular energy supply and metabolism. Biomedicines 8, 526 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Pessayre, D. et al. Central role of mitochondria in drug-induced liver injury. Drug. Metab. Rev. 44, 34–87 (2012).

    Article  CAS  PubMed  Google Scholar 

  76. Gusdon, A. M., Song, K. & Qu, S. Nonalcoholic fatty liver disease: pathogenesis and therapeutics from a mitochondria-centric perspective. Oxid. Med. Cell Longev. https://doi.org/10.1155/2014/637027. (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  77. McGarry, J. D. & Foster, D. W. Regulation of hepatic fatty acid oxidation and ketone body production. Annu. Rev. Biochem. 49, 395–420 (1980).

    Article  CAS  PubMed  Google Scholar 

  78. Zorov, D. B., Juhaszova, M. & Sollott, S. J. Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release. Physiol. Rev. 94, 909–950 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Kotiadis, V. N., Duchen, M. R. & Osellame, L. D. Mitochondrial quality control and communications with the nucleus are important in maintaining mitochondrial function and cell health. Biochim. Biophys. Acta 1840, 1254–1265 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Tell, G., Vascotto, C. & Tiribelli, C. Alterations in the redox state and liver damage: hints from the EASL Basic School of Hepatology. J. Hepatol. 58, 365–374 (2013).

    Article  PubMed  Google Scholar 

  81. Kakimoto, P. A. H. B., Tamaki, F. K., Cardoso, A. R., Marana, S. R. & Kowaltowski, A. J. H2O2 release from the very long chain acyl-CoA dehydrogenase. Redox Biol. 4, 375–380 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Auten, R. L. & Davis, J. M. Oxygen toxicity and reactive oxygen species: the devil is in the details. Pediatr. Res. 66, 121–127 (2009).

    Article  CAS  PubMed  Google Scholar 

  83. Forman, H. J., Maiorino, M. & Ursini, F. Signaling functions of reactive oxygen species. Biochemistry 49, 835–842 (2010).

    Article  CAS  PubMed  Google Scholar 

  84. Dröge, W. Free radicals in the physiological control of cell function. Physiol. Rev. 82, 47–95 (2002).

    Article  PubMed  Google Scholar 

  85. Finkel, T. Signal transduction by mitochondrial oxidants. J. Biol. Chem. 287, 4434–4440 (2012).

    Article  CAS  PubMed  Google Scholar 

  86. Meakin, P. J. et al. Susceptibility of Nrf2-null mice to steatohepatitis and cirrhosis upon consumption of a high-fat diet is associated with oxidative stress, perturbation of the unfolded protein response, and disturbance in the expression of metabolic enzymes but not with insulin resistance. Mol. Cell Biol. 34, 3305–3320 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  87. Win, S. et al. New insights into the role and mechanism of c-Jun-N-terminal kinase signaling in the pathobiology of liver diseases. Hepatology 67, 2013–2024 (2018).

    Article  PubMed  Google Scholar 

  88. 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  CAS  PubMed  Google Scholar 

  89. Franko, A. et al. Liver adapts mitochondrial function to insulin resistant and diabetic states in mice. J. Hepatol. 60, 816–823 (2014).

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  91. Cortez-Pinto, H. et al. Alterations in liver ATP homeostasis in human nonalcoholic steatohepatitis: a pilot study. JAMA 282, 1659–1664 (1999).

    Article  CAS  PubMed  Google Scholar 

  92. Ramirez-Tortosa, M. C. et al. Curcumin ameliorates rabbits’s steatohepatitis via respiratory chain, oxidative stress, and TNF-α. Free. Radic. Biol. Med. 47, 924–931 (2009).

    Article  CAS  PubMed  Google Scholar 

  93. Li, S. et al. Nobiletin mitigates hepatocytes death, liver inflammation, and fibrosis in a murine model of NASH through modulating hepatic oxidative stress and mitochondrial dysfunction. J. Nutr. Biochem. 100, 108888 (2022).

    Article  CAS  PubMed  Google Scholar 

  94. 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  CAS  PubMed  Google Scholar 

  95. Koliaki, C. & Roden, M. Hepatic energy metabolism in human diabetes mellitus, obesity and non-alcoholic fatty liver disease. Mol. Cell. Endocrinol. 379, 35–42 (2013).

    Article  CAS  PubMed  Google Scholar 

  96. Morris, E. M., Rector, R. S., Thyfault, J. P. & Ibdah, J. A. Mitochondria and redox signaling in steatohepatitis. Antioxid. Redox Signal. 15, 485–504 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Loskovich, M. V., Grivennikova, V. G., Cecchini, G. & Vinogradov, A. D. Inhibitory effect of palmitate on the mitochondrial NADH:ubiquinone oxidoreductase (complex I) as related to the active–de-active enzyme transition. Biochem. J. 387, 677–683 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Cocco, T., Di, M., Papa, P. & Lorusso, M. Arachidonic acid interaction with the mitochondrial electron transport chain promotes reactive oxygen species generation. Free. Radic. Biol. Med. 27, 51–59 (1999).

    Article  CAS  PubMed  Google Scholar 

  99. Begriche, K., Igoudjil, A., Pessayre, D. & Fromenty, B. Mitochondrial dysfunction in NASH: causes, consequences and possible means to prevent it. Mitochondrion 6, 1–28 (2006).

    Article  CAS  PubMed  Google Scholar 

  100. Kirsch, R. et al. Rodent nutritional model of non-alcoholic steatohepatitis: species, strain and sex difference studies. J. Gastroenterol. Hepatol. 18, 1272–1282 (2003).

    Article  PubMed  Google Scholar 

  101. Larosche, I. et al. Prolonged ethanol administration depletes mitochondrial DNA in MnSOD-overexpressing transgenic mice, but not in their wild type littermates. Toxicol. Appl. Pharmacol. 234, 326–338 (2009).

    Article  CAS  PubMed  Google Scholar 

  102. Larosche, I. et al. Hepatic mitochondrial DNA depletion after an alcohol binge in mice: probable role of peroxynitrite and modulation by manganese superoxide dismutase. J. Pharmacol. Exp. Ther. 332, 886–897 (2010).

    Article  CAS  PubMed  Google Scholar 

  103. Chen, J., Schenker, S., Frosto, T. A. & Henderson, G. I. Inhibition of cytochrome c oxidase activity by 4-hydroxynonenal (HNE). Biochim. Biophys. Acta 1380, 336–344 (1998).

    Article  CAS  PubMed  Google Scholar 

  104. Zhang, Q. et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 464, 104–107 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. An, P. et al. Hepatocyte mitochondria-derived danger signals directly activate hepatic stellate cells and drive progression of liver fibrosis. Nat. Commun. 11, 2362 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Knockaert, L., Fromenty, B. & Robin, M.-A. Mechanisms of mitochondrial targeting of cytochrome P450 2E1: physiopathological role in liver injury and obesity. FEBS J. 278, 4252–4260 (2011).

    Article  CAS  PubMed  Google Scholar 

  107. Robin, M.-A. et al. Bimodal targeting of microsomal CYP2E1 to mitochondria through activation of an N-terminal chimeric signal by cAMP-mediated phosphorylation. J. Biol. Chem. 277, 40583–40593 (2002).

    Article  CAS  PubMed  Google Scholar 

  108. Koop, D. R. Oxidative and reductive metabolism by cytochrome P450 2E1. FASEB J. 6, 724–730 (1992).

    Article  CAS  PubMed  Google Scholar 

  109. Harjumäki, R., Pridgeon, C. S. & Ingelman-Sundberg, M. CYP2E1 in alcoholic and non-alcoholic liver injury. roles of ROS, reactive intermediates and lipid overload. Int. J. Mol. Sci. 22, 8221 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  110. Johansson, I. & Ingelman-Sundberg, M. Carbon tetrachloride-induced lipid peroxidation dependent on an ethanol-inducible form of rabbit liver microsomal cytochrome P-450. FEBS Lett. 183, 265–269 (1985).

    Article  CAS  PubMed  Google Scholar 

  111. Aubert, J., Begriche, K., Knockaert, L., Robin, M. A. & Fromenty, B. Increased expression of cytochrome P450 2E1 in nonalcoholic fatty liver disease: mechanisms and pathophysiological role. Clin. Res. Hepatol. Gastroenterol. 35, 630–637 (2011).

    Article  CAS  PubMed  Google Scholar 

  112. Emery, M. CYP2E1 activity before and after weight loss in morbidly obese subjects with nonalcoholic fatty liver disease. Hepatology 38, 428–435 (2003).

    Article  CAS  PubMed  Google Scholar 

  113. Weltman, M. D., Farrell, G. C., Hall, P., Ingelman-Sundberg, M. & Liddle, C. Hepatic cytochrome P450 2E1 is increased in patients with nonalcoholic steatohepatitis. Hepatology 27, 128–133 (1998).

    Article  CAS  PubMed  Google Scholar 

  114. Khemawoot, P., Yokogawa, K., Shimada, T. & Miyamoto, K. Obesity-induced increase of CYP2E1 activity and its effect on disposition kinetics of chlorzoxazone in Zucker rats. Biochem. Pharmacol. 73, 155–162 (2007).

    Article  CAS  PubMed  Google Scholar 

  115. Chalasani, N. Hepatic cytochrome P450 2E1 activity in nondiabetic patients with nonalcoholic steatohepatitis. Hepatology 37, 544–550 (2003).

    Article  CAS  PubMed  Google Scholar 

  116. Seth, R. K. et al. M1 polarization bias and subsequent nonalcoholic steatohepatitis progression is attenuated by nitric oxide donor DETA NONOate via inhibition of CYP2E1-induced oxidative stress in obese mice. J. Pharmacol. Exp. Ther. 352, 77–89 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  117. Abdelmegeed, M. A. et al. Critical role of cytochrome P450 2E1 (CYP2E1) in the development of high fat-induced non-alcoholic steatohepatitis. J. Hepatol. 57, 860–866 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Abdelmegeed, M. A. et al. Cytochrome P450-2E1 promotes fast food-mediated hepatic fibrosis. Sci. Rep. 7, 39764 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Cho, Y.-E. et al. Fructose promotes leaky gut, endotoxemia and liver fibrosis through CYP2E1-mediated oxidative and nitrative stress. Hepatology 73, 2180–2195 (2021).

    Article  CAS  PubMed  Google Scholar 

  120. Videla, L. A., Rodrigo, R., Araya, J. & Poniachik, J. Oxidative stress and depletion of hepatic long-chain polyunsaturated fatty acids may contribute to nonalcoholic fatty liver disease. Free. Radic. Biol. Med. 37, 1499–1507 (2004).

    Article  CAS  PubMed  Google Scholar 

  121. Bansal, S. et al. Mitochondria-targeted cytochrome P450 2E1 induces oxidative damage and augments alcohol-mediated oxidative stress. J. Biol. Chem. 285, 24609–24619 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Knockaert, L., Descatoire, V., Vadrot, N., Fromenty, B. & Robin, M.-A. Mitochondrial CYP2E1 is sufficient to mediate oxidative stress and cytotoxicity induced by ethanol and acetaminophen. Toxicol. Vitr. 25, 475–484 (2011).

    Article  CAS  Google Scholar 

  123. Turrens, J. F. Mitochondrial formation of reactive oxygen species. J. Physiol. 552, 335–344 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Cadenas, E. & Davies, K. J. A. Mitochondrial free radical generation, oxidative stress, and aging. Free. Radic. Biol. Med. 29, 222–230 (2000).

    Article  CAS  PubMed  Google Scholar 

  125. Yadav, U. C. S. & Ramana, K. V. Regulation of NF-κB-induced inflammatory signaling by lipid peroxidation-derived aldehydes. Oxid. Med. Cell. Longev. 2013, 690545 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  126. Meyer, M., Pahl, H. L. & Baeuerle, P. A. Regulation of the transcription factors NF-κB and AP-1 by redox changes. Chem. Biol. Interact. 91, 91–100 (1994).

    Article  CAS  PubMed  Google Scholar 

  127. Nakajima, S. & Kitamura, M. Bidirectional regulation of NF-κB by reactive oxygen species: a role of unfolded protein response. Free. Radic. Biol. Med. 65, 162–174 (2013).

    Article  CAS  PubMed  Google Scholar 

  128. Herzig, S. & Shaw, R. J. AMPK: guardian of metabolism and mitochondrial homeostasis. Nat. Rev. Mol. Cell Biol. 19, 121–135 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  129. Schattenberg, J. M. et al. Jnk1 but not jnk2 promotes the development of steatohepatitis in mice. Hepatology 43, 163–172 (2006).

    Article  CAS  PubMed  Google Scholar 

  130. Kamata, H. et al. Reactive oxygen species promote TNFα-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases. Cell 120, 649–661 (2005).

    Article  CAS  PubMed  Google Scholar 

  131. Win, S. et al. Sab (Sh3bp5) dependence of JNK mediated inhibition of mitochondrial respiration in palmitic acid induced hepatocyte lipotoxicity. J. Hepatol. 62, 1367–1374 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Win, S. et al. Hepatic mitochondrial SAB deletion or knockdown alleviates diet‐induced metabolic syndrome, steatohepatitis, and hepatic fibrosis. Hepatology 74, 3127–3145 (2021).

    Article  CAS  PubMed  Google Scholar 

  133. Huo, Y. et al. Antcin H protects against acute liver injury through disruption of the interaction of c-Jun-N-terminal kinase with mitochondria. Antioxid. Redox Signal. 26, 207–220 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Urbina-Varela, R., Castillo, N., Videla, L. A. & del Campo, A. Impact of mitophagy and mitochondrial unfolded protein response as new adaptive mechanisms underlying old pathologies: sarcopenia and non-alcoholic fatty liver disease. Int. J. Mol. Sci. 21, 7704 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Madrigal-Matute, J. & Cuervo, A. M. Regulation of liver metabolism by autophagy. Gastroenterology 150, 328–339 (2016).

    Article  CAS  PubMed  Google Scholar 

  136. Tsurusaki, S. et al. Hepatic ferroptosis plays an important role as the trigger for initiating inflammation in nonalcoholic steatohepatitis. Cell Death Dis. 10, 449 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  137. Qi, J., Kim, J.-W., Zhou, Z., Lim, C.-W. & Kim, B. Ferroptosis affects the progression of nonalcoholic steatohepatitis via the modulation of lipid peroxidation-mediated cell death in mice. Am. J. Pathol. 190, 68–81 (2020).

    Article  CAS  PubMed  Google Scholar 

  138. Yu, Y. et al. Hepatic transferrin plays a role in systemic iron homeostasis and liver ferroptosis. Blood 136, 726–739 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. 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  CAS  PubMed  Google Scholar 

  140. Koo, J. H., Lee, H. J., Kim, W. & Kim, S. G. Endoplasmic reticulum stress in hepatic stellate cells promotes liver fibrosis via PERK-mediated degradation of HNRNPA1 and up-regulation of SMAD2. Gastroenterology 150, 181–193.e8 (2016).

    Article  CAS  PubMed  Google Scholar 

  141. Ma, Z. et al. Resveratrol alleviates hepatic fibrosis in associated with decreased endoplasmic reticulum stress-mediated apoptosis and inflammation. Inflammation 45, 812–823 (2022).

    Article  CAS  PubMed  Google Scholar 

  142. Mencin, A. et al. Alpha-1 antitrypsin Z protein (PiZ) increases hepatic fibrosis in a murine model of cholestasis. Hepatology 46, 1443–1452 (2007).

    Article  CAS  PubMed  Google Scholar 

  143. Tamaki, N. et al. CHOP deficiency attenuates cholestasis-induced liver fibrosis by reduction of hepatocyte injury. Am. J. Physiol. Gastrointest. Liver Physiol. 294, G498–G505 (2008).

    Article  CAS  PubMed  Google Scholar 

  144. Iracheta-Vellve, A. et al. Endoplasmic reticulum stress-induced hepatocellular death pathways mediate liver injury and fibrosis via stimulator of interferon genes. J. Biol. Chem. 291, 26794–26805 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Thomsen, M. K. et al. Lack of immunological DNA sensing in hepatocytes facilitates hepatitis B virus infection. Hepatology 64, 746–759 (2016).

    Article  CAS  PubMed  Google Scholar 

  146. Maher, J. J. Macrophages steal STING from the infectious disease playbook to promote nonalcoholic fatty liver disease. Gastroenterology 155, 1687–1688 (2018).

    Article  PubMed  Google Scholar 

  147. Siao, K., Le Guillou, D., Maher, J. J. & Duwaerts, C. C. The role of STING in liver injury is both stimulus- and time-dependent. Nutrients 14, 4029 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Diamond, D. L. et al. Proteomic profiling of human liver biopsies: hepatitis C virus-induced fibrosis and mitochondrial dysfunction. Hepatology 46, 649–657 (2007).

    Article  CAS  PubMed  Google Scholar 

  149. Loureiro, D. et al. Mitochondrial stress in advanced fibrosis and cirrhosis associated with chronic hepatitis B, chronic hepatitis C, or nonalcoholic steatohepatitis. Hepatology 77, 1348–1365 (2022).

    Article  PubMed  Google Scholar 

  150. Rehman, H. et al. The mitochondria-targeted antioxidant MitoQ attenuates liver fibrosis in mice. Int. J. Physiol. Pathophysiol. Pharmacol. 8, 14–27 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Mitchell, C. et al. Protection against hepatocyte mitochondrial dysfunction delays fibrosis progression in mice. Am. J. Pathol. 175, 1929–1937 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Song, M. et al. Augmenter of liver regeneration (ALR) gene therapy attenuates CCl4-induced liver injury and fibrosis in rats. Biochem. Biophys. Res. Commun. 415, 152–156 (2011).

    Article  CAS  PubMed  Google Scholar 

  153. Krähenbühl, L., Ledermann, M., Lang, C. & Krähenbühl, S. Relationship between hepatic mitochondrial functions in vivo and in vitro in rats with carbon tetrachloride-induced liver cirrhosis. J. Hepatol. 33, 216–223 (2000).

    Article  PubMed  Google Scholar 

  154. Melin, N. et al. A new mouse model of radiation-induced liver disease reveals mitochondrial dysfunction as an underlying fibrotic stimulus. JHEP Rep. 4, 100508 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  155. Shan, S. et al. Drp1-mediated mitochondrial fission promotes carbon tetrachloride-induced hepatic fibrogenesis in mice. Toxicol. Res. 11, 486–497 (2022).

    Article  Google Scholar 

  156. Zhang, L., Zhang, Y., Chang, X. & Zhang, X. Imbalance in mitochondrial dynamics induced by low PGC-1α expression contributes to hepatocyte EMT and liver fibrosis. Cell Death Dis. 11, 226 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Scarpulla, R. C., Vega, R. B. & Kelly, D. P. Transcriptional integration of mitochondrial biogenesis. Trends Endocrinol. Metab. 23, 459–466 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Xu, J. et al. The role of human cytochrome P450 2E1 in liver inflammation and fibrosis. Hepatol. Commun. 1, 1043–1057 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Gao, J. et al. High CYP2E1 activity correlates with hepatofibrogenesis induced by nitrosamines. Oncotarget 8, 112199–112210 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  160. Mannaerts, I. et al. Unfolded protein response is an early, non-critical event during hepatic stellate cell activation. Cell Death Dis. 10, 98 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  161. Heindryckx, F. et al. Endoplasmic reticulum stress enhances fibrosis through IRE1α-mediated degradation of miR-150 and XBP-1 splicing. EMBO Mol. Med. 8, 729–744 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Liu, Z. et al. Transforming growth factor β (TGFβ) cross-talk with the unfolded protein response is critical for hepatic stellate cell activation. J. Biol. Chem. 294, 3137–3151 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Hernández-Gea, V. et al. Endoplasmic reticulum stress induces fibrogenic activity in hepatic stellate cells through autophagy. J. Hepatol. 59, 98–104 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  164. Hernández-Gea, V. et al. Autophagy releases lipid that promotes fibrogenesis by activated hepatic stellate cells in mice and in human tissues. Gastroenterology 142, 938–946 (2012).

    Article  PubMed  Google Scholar 

  165. Kim, R. S. et al. The XBP1 arm of the unfolded protein response induces fibrogenic activity in hepatic stellate cells through autophagy. Sci. Rep. 6, 39342 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Ruiz de Galarreta, M. et al. Unfolded protein response induced by Brefeldin A increases collagen type I levels in hepatic stellate cells through an IRE1α, p38 MAPK and Smad-dependent pathway. Biochim. Biophys. Acta 1863, 2115–2123 (2016).

    Article  Google Scholar 

  167. Maiers, J. L. et al. The unfolded protein response mediates fibrogenesis and collagen I secretion through regulating TANGO1 in mice. Hepatology 65, 983–998 (2017).

    Article  CAS  PubMed  Google Scholar 

  168. Lim, M. P., Devi, L. A. & Rozenfeld, R. Cannabidiol causes activated hepatic stellate cell death through a mechanism of endoplasmic reticulum stress-induced apoptosis. Cell Death Dis. 2, e170 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Li, Y. et al. Autophagy mediated by endoplasmic reticulum stress enhances the caffeine-induced apoptosis of hepatic stellate cells. Int. J. Mol. Med. 40, 1405–1414 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Kawasaki, K. et al. Deletion of the collagen-specific molecular chaperone Hsp47 causes endoplasmic reticulum stress-mediated apoptosis of hepatic stellate cells. J. Biol. Chem. 290, 3639–3646 (2015).

    Article  CAS  PubMed  Google Scholar 

  171. Smith-Cortinez, N. et al. Simultaneous induction of glycolysis and oxidative phosphorylation during activation of hepatic stellate cells reveals novel mitochondrial targets to treat liver fibrosis. Cells 9, 2456 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Bae, M. et al. Astaxanthin attenuates the increase in mitochondrial respiration during the activation of hepatic stellate cells. J. Nutr. Biochem. 71, 82–89 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Chen, M.-F. et al. Saikosaponin d induces cell death through caspase-3-dependent, caspase-3-independent and mitochondrial pathways in mammalian hepatic stellate cells. BMC Cancer 16, 532 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  174. Guimarães, E. L. et al. Mitochondrial uncouplers inhibit hepatic stellate cell activation. BMC Gastroenterol. 12, 68 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  175. Greenwel, P., Domínguez-Rosales, J.-A., Mavi, G., Rivas-Estilla, A. M. & Rojkind, M. Hydrogen peroxide: a link between acetaldehyde-elicited α1(i) collagen gene up-regulation and oxidative stress in mouse hepatic stellate cells. Hepatology 31, 109–116 (2000).

    Article  CAS  PubMed  Google Scholar 

  176. Lan, T., Kisseleva, T. & Brenner, D. A. Deficiency of NOX1 or NOX4 prevents liver inflammation and fibrosis in mice through inhibition of hepatic stellate cell activation. PLoS ONE 10, e0129743 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  177. Paik, Y.-H. et al. The nicotinamide adenine dinucleotide phosphate oxidase (NOX) homologues NOX1 and NOX2/gp91phox mediate hepatic fibrosis in mice. Hepatology 53, 1730–1741 (2011).

    Article  CAS  PubMed  Google Scholar 

  178. Sancho, P. et al. NADPH oxidase NOX4 mediates stellate cell activation and hepatocyte cell death during liver fibrosis development. PLoS ONE 7, e45285 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Sasaki, Y. et al. NOX4 regulates CCR2 and CCL2 mRNA stability in alcoholic liver disease. Sci. Rep. 7, 46144 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Van Thuy, T. T., Thuy, L. T. T., Yoshizato, K. & Kawada, N. Possible involvement of nitric oxide in enhanced liver injury and fibrogenesis during cholestasis in cytoglobin-deficient mice. Sci. Rep. 7, 41888 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  181. Thuy, L. T. T. et al. Promotion of liver and lung tumorigenesis in DEN-treated cytoglobin-deficient mice. Am. J. Pathol. 179, 1050–1060 (2011).

    Article  CAS  PubMed  Google Scholar 

  182. Thuy, L. T. T. et al. Cytoglobin deficiency promotes liver cancer development from hepatosteatosis through activation of the oxidative stress pathway. Am. J. Pathol. 185, 1045–1060 (2015).

    Article  CAS  PubMed  Google Scholar 

  183. Thuy, L. T. T. et al. Absence of cytoglobin promotes multiple organ abnormalities in aged mice. Sci. Rep. 6, 24990 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Okina, Y. et al. TGF-β1-driven reduction of cytoglobin leads to oxidative DNA damage in stellate cells during non-alcoholic steatohepatitis. J. Hepatol. 73, 882–895 (2020).

    Article  CAS  PubMed  Google Scholar 

  185. Inzaugarat, M. E. et al. NLR family pyrin domain-containing 3 inflammasome activation in hepatic stellate cells induces liver fibrosis in mice. Hepatology 69, 845–859 (2019).

    Article  CAS  PubMed  Google Scholar 

  186. Knorr, J. et al. Interleukin‐18 signaling promotes activation of hepatic stellate cells in mouse liver fibrosis. Hepatology 77, 1968–1972 (2023).

    Article  PubMed  Google Scholar 

  187. Zhao, Y. et al. p66Shc contributes to liver fibrosis through the regulation of mitochondrial reactive oxygen species. Theranostics 9, 1510–1522 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Cai, S.-M. et al. Angiotensin-(1–7) improves liver fibrosis by regulating the NLRP3 inflammasome via redox balance modulation. Antioxid. Redox Signal. 24, 795–812 (2016).

    Article  CAS  PubMed  Google Scholar 

  189. Jiang, S. et al. Potentiation of hepatic stellate cell activation by extracellular ATP is dependent on P2X7R-mediated NLRP3 inflammasome activation. Pharmacol. Res. 117, 82–93 (2017).

    Article  CAS  PubMed  Google Scholar 

  190. Foo, N.-P., Lin, S.-H., Lee, Y.-H., Wu, M.-J. & Wang, Y.-J. α-Lipoic acid inhibits liver fibrosis through the attenuation of ROS-triggered signaling in hepatic stellate cells activated by PDGF and TGF-β. Toxicology 282, 39–46 (2011).

    Article  CAS  PubMed  Google Scholar 

  191. Jia, D. et al. Pyrroloquinoline-quinone suppresses liver fibrogenesis in mice. PLoS ONE 10, e0121939 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  192. Xie, Z.-Y., Xiao, Z.-H. & Wang, F.-F. Inhibition of autophagy reverses alcohol-induced hepatic stellate cells activation through activation of Nrf2-Keap1-ARE signaling pathway. Biochimie 147, 55–62 (2018).

    Article  CAS  PubMed  Google Scholar 

  193. Zhou, Y. et al. Oxidative stress-mediated mitochondrial fission promotes hepatic stellate cell activation via stimulating oxidative phosphorylation. Cell Death Dis. 13, 689 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Su, Y. et al. Metformin induces mitochondrial fission and reduces energy metabolism by targeting respiratory chain complex I in hepatic stellate cells to reverse liver fibrosis. Int. J. Biochem. Cell Biol. 157, 106375 (2023).

    Article  CAS  PubMed  Google Scholar 

  195. Zhu, H. et al. Specific overexpression of mitofusin-2 in hepatic stellate cells ameliorates liver fibrosis in mice model. Hum. Gene Ther. 31, 103–109 (2020).

    Article  CAS  PubMed  Google Scholar 

  196. Ai, W. et al. Deficiency in augmenter of liver regeneration accelerates liver fibrosis by promoting migration of hepatic stellate cell. Biochim. Biophys. Acta 1864, 3780–3791 (2018).

    Article  CAS  Google Scholar 

  197. Wang, Z.-J. et al. PM2.5 promotes Drp1-mediated mitophagy to induce hepatic stellate cell activation and hepatic fibrosis via regulating miR-411. Exp. Cell Res. 407, 112828 (2021).

    Article  CAS  PubMed  Google Scholar 

  198. Dou, S.-Y. et al. MitoQ inhibits hepatic stellate cell activation and liver fibrosis by enhancing PINK1/parkin-mediated mitophagy. Open Med. 16, 1718–1727 (2021).

    Article  CAS  Google Scholar 

  199. Ding, Q. et al. The role of the apoptosis-related protein BCL-B in the regulation of mitophagy in hepatic stellate cells during the regression of liver fibrosis. Exp. Mol. Med. 51, 1–13 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Duong, H. T. T. et al. The use of nanoparticles to deliver nitric oxide to hepatic stellate cells for treating liver fibrosis and portal hypertension. Small 11, 2291–2304 (2015).

    Article  CAS  PubMed  Google Scholar 

  201. Zhang, M. et al. Arginase 1 expression is increased during hepatic stellate cell activation and facilitates collagen synthesis. J. Cell. Biochem. 124, 808–817 (2023).

    Article  CAS  PubMed  Google Scholar 

  202. Lukivskaya, O., Patsenker, E., Lis, R. & Buko, V. U. Inhibition of inducible nitric oxide synthase activity prevents liver recovery in rat thioacetamide-induced fibrosis reversal. Eur. J. Clin. Invest. 38, 317–325 (2008).

    Article  CAS  PubMed  Google Scholar 

  203. Dong, Z. et al. Adiponectin attenuates liver fibrosis by inducing nitric oxide production of hepatic stellate cells. J. Mol. Med. 93, 1327–1339 (2015).

    Article  CAS  PubMed  Google Scholar 

  204. Haas, M. J., Feng, V., Gonzales, K., Onstead-Haas, L. & Mooradian, A. D. High-throughput analysis identifying drugs that reduce oxidative and ER stress in human coronary artery endothelial cells. Eur. J. Pharmacol. 879, 173119 (2020).

    Article  CAS  PubMed  Google Scholar 

  205. Zhong, Y. et al. Endoplasmic reticulum stress-induced endothelial dysfunction promotes neointima formation after arteriovenous grafts in mice on high-fat diet. Curr. Med. Sci. 43, 115–122 (2023).

    Article  CAS  PubMed  Google Scholar 

  206. Bodenheimer, H. The sinusoids in human liver: health and disease. Edited by Paulette Bioulac-Sage and Charles Balabaud, 393 pp. The Netherlands: Stichting Kupffer Cell Foundation, 1988. Hepatology 10, 395–396 (1989).

    Article  Google Scholar 

  207. Horn, T., Christoffersen, P. & Henriksen, J. H. Alcoholic liver injury: defenestration in noncirrhotic livers – a scanning electron microscopic study. Hepatology 7, 77–82 (1987).

    Article  CAS  PubMed  Google Scholar 

  208. Fraser, R. et al. in Cells of the Hepatic Sinusoid Vol. 3 (eds Wisse, E., Knook, D. L. & McCuskey, R. S.) 195–198 (Kupffer Cell Foundation, 1991).

  209. DeLeve, L. D. & Maretti-Mira, A. C. Liver sinusoidal endothelial cell: an update. Semin. Liver Dis. 37, 377–387 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  210. DeLeve, L. D., Wang, X. & Guo, Y. Sinusoidal endothelial cells prevent rat stellate cell activation and promote reversion to quiescence. Hepatology 48, 920–930 (2008).

    Article  CAS  PubMed  Google Scholar 

  211. Xie, G. et al. Role of differentiation of liver sinusoidal endothelial cells in progression and regression of hepatic fibrosis in rats. Gastroenterology 142, 918–927.e6 (2012).

    Article  PubMed  Google Scholar 

  212. DeLeve, L. D., Wang, X., Hu, L., McCuskey, M. K. & McCuskey, R. S. Rat liver sinusoidal endothelial cell phenotype is maintained by paracrine and autocrine regulation. Am. J. Physiol. Gastrointest. Liver Physiol. 287, G757–G763 (2004).

    Article  CAS  PubMed  Google Scholar 

  213. Gracia-Sancho, J. et al. Increased oxidative stress in cirrhotic rat livers: a potential mechanism contributing to reduced nitric oxide bioavailability. Hepatology 47, 1248–1256 (2008).

    Article  CAS  PubMed  Google Scholar 

  214. Gonzalez-Paredes, F. J. et al. Contribution of cyclooxygenase end products and oxidative stress to intrahepatic endothelial dysfunction in early non-alcoholic fatty liver disease. PLoS ONE 11, e0156650 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  215. Su, T. et al. Single-cell transcriptomics reveals zone-specific alterations of liver sinusoidal endothelial cells in cirrhosis. Cell. Mol. Gastroenterol. Hepatol. 11, 1139–1161 (2021).

    Article  PubMed  Google Scholar 

  216. Matsumoto, M. et al. The NOX1 isoform of NADPH oxidase is involved in dysfunction of liver sinusoids in nonalcoholic fatty liver disease. Free. Radic. Biol. Med. 115, 412–420 (2018).

    Article  CAS  PubMed  Google Scholar 

  217. Yang, Y. et al. Alcohol-induced Hsp90 acetylation is a novel driver of liver sinusoidal endothelial dysfunction and alcohol-related liver disease. J. Hepatol. 75, 377–386 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Ruart, M. et al. Impaired endothelial autophagy promotes liver fibrosis by aggravating the oxidative stress response during acute liver injury. J. Hepatol. 70, 458–469 (2019).

    Article  CAS  PubMed  Google Scholar 

  219. Hammoutene, A. et al. A defect in endothelial autophagy occurs in patients with non-alcoholic steatohepatitis and promotes inflammation and fibrosis. J. Hepatol. 72, 528–538 (2020).

    Article  CAS  PubMed  Google Scholar 

  220. Wen, Y., Lambrecht, J., Ju, C. & Tacke, F. Hepatic macrophages in liver homeostasis and diseases – diversity, plasticity and therapeutic opportunities. Cell. Mol. Immunol. 18, 45–56 (2021).

    Article  CAS  PubMed  Google Scholar 

  221. Wang, W., Xu, X. & Miao, C. Kupffer cell-derived TNF-α triggers the apoptosis of hepatic stellate cells through TNF-R1/caspase 8 due to ER stress. Biomed. Res. Int. 2020, 8035671 (2020).

    PubMed  PubMed Central  Google Scholar 

  222. Park, J.-K. et al. An endoplasmic reticulum protein, Nogo-B, facilitates alcoholic liver disease through regulation of Kupffer cell polarization. Hepatology 65, 1720–1734 (2017).

    Article  CAS  PubMed  Google Scholar 

  223. Wang, Q. et al. Role of XBP1 in regulating the progression of non-alcoholic steatohepatitis. J. Hepatol. 77, 312–325 (2022).

    Article  CAS  PubMed  Google Scholar 

  224. Liang, S., Kisseleva, T. & Brenner, D. A. The role of NADPH oxidases (NOXs) in liver fibrosis and the activation of myofibroblasts. Front. Physiol. 7, 17 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  226. Nieto, N. Oxidative-stress and IL-6 mediate the fibrogenic effects of rodent Kupffer cells on stellate cells. Hepatology 44, 1487–1501 (2006).

    Article  CAS  PubMed  Google Scholar 

  227. Wu, H. et al. TIM-4 interference in Kupffer cells against CCL4-induced liver fibrosis by mediating Akt1/mitophagy signalling pathway. Cell Prolif. 53, e12731 (2020).

    Article  PubMed  Google Scholar 

  228. Liu, Y. et al. S100A8-mediated NLRP3 inflammasome-dependent pyroptosis in macrophages facilitates liver fibrosis progression. Cells 11, 3579 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. He, K. et al. Inhibition of NLRP3 inflammasome by thioredoxin-interacting protein in mouse Kupffer cells as a regulatory mechanism for non-alcoholic fatty liver disease development. Oncotarget 8, 37657–37672 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  230. Pan, J. et al. Fatty acid activates NLRP3 inflammasomes in mouse Kupffer cells through mitochondrial DNA release. Cell. Immunol. 332, 111–120 (2018).

    Article  CAS  PubMed  Google Scholar 

  231. Kaufmann, B. et al. Cell-specific deletion of NLRP3 inflammasome identifies myeloid cells as key drivers of liver inflammation and fibrosis in murine steatohepatitis. Cell. Mol. Gastroenterol. Hepatol. 14, 751–767 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Handa, P. et al. Iron alters macrophage polarization status and leads to steatohepatitis and fibrogenesis. J. Leukoc. Biol. 105, 1015–1026 (2019).

    Article  CAS  PubMed  Google Scholar 

  233. Kanamori, Y. et al. Iron-rich Kupffer cells exhibit phenotypic changes during the development of liver fibrosis in NASH. iScience 24, 102032 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Sharma, S., Le Guillou, D. & Chen, J.Y. Cellular stress in the pathogenesis of nonalcoholic steatohepatitis and liver fibrosis. Nat Rev Gastroenterol Hepatol 20, 662–678 (2023). https://doi.org/10.1038/s41575-023-00832-w

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