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
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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.
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Mitochondrial dysfunction and oxidative stress drive NASH and liver fibrosis by causing hepatocyte damage, immune cell activation and inflammation.
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Cellular stress pathways in hepatocytes also contribute to fibrogenesis independent of NASH.
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Intracellular reactive oxygen species generation provokes endoplasmic reticulum stress and autophagy that contribute to the activation of hepatic stellate cells.
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References
Cheemerla, S. & Balakrishnan, M. Global epidemiology of chronic liver disease. Clin. Liver Dis. 17, 365–370 (2021).
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).
Kisseleva, T. & Brenner, D. Molecular and cellular mechanisms of liver fibrosis and its regression. Nat. Rev. Gastroenterol. Hepatol. 18, 151–166 (2021).
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).
Iwaisako, K. et al. Origin of myofibroblasts in the fibrotic liver in mice. Proc. Natl Acad. Sci. USA 111, E3297–E3305 (2014).
Friedman, S. L. Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol. Rev. 88, 125–172 (2008).
Ramachandran, P. et al. Resolving the fibrotic niche of human liver cirrhosis at single-cell level. Nature 575, 512–518 (2019).
Tilg, H. & Moschen, A. R. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology 52, 1836–1846 (2010).
Baiceanu, A., Mesdom, P., Lagouge, M. & Foufelle, F. Endoplasmic reticulum proteostasis in hepatic steatosis. Nat. Rev. Endocrinol. 12, 710–722 (2016).
Lebeaupin, C. et al. Endoplasmic reticulum stress signalling and the pathogenesis of non-alcoholic fatty liver disease. J. Hepatol. 69, 927–947 (2018).
Wang, M. & Kaufman, R. J. Protein misfolding in the endoplasmic reticulum as a conduit to human disease. Nature 529, 326–335 (2016).
Hetz, C., Chevet, E. & Oakes, S. A. Proteostasis control by the unfolded protein response. Nat. Cell Biol. 17, 829–838 (2015).
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).
Calfon, M. et al. IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature 415, 92–96 (2002).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Ajoolabady, A. et al. Endoplasmic reticulum stress in liver diseases. Hepatology 77, 619–639 (2022).
Han, J. & Kaufman, R. J. The role of ER stress in lipid metabolism and lipotoxicity. J. Lipid Res. 57, 1329–1338 (2016).
Pagliassotti, M. J. Endoplasmic reticulum stress in nonalcoholic fatty liver disease. Annu. Rev. Nutr. 32, 17–33 (2012).
Cazanave, S. C. et al. Death receptor 5 signaling promotes hepatocyte lipoapoptosis. J. Biol. Chem. 286, 39336–39348 (2011).
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).
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).
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).
Puri, P. et al. Activation and dysregulation of the unfolded protein response in nonalcoholic fatty liver disease. Gastroenterology 134, 568–576 (2008).
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).
Lebeaupin, C. et al. ER stress induces NLRP3 inflammasome activation and hepatocyte death. Cell Death Dis. 6, e1879 (2015).
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).
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).
Sanyal, A. J. et al. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology 120, 1183–1192 (2001).
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).
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).
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).
Akazawa, Y. et al. Palmitoleate attenuates palmitate-induced Bim and PUMA up-regulation and hepatocyte lipoapoptosis. J. Hepatol. 52, 586–593 (2010).
Szabo, G. & Petrasek, J. Inflammasome activation and function in liver disease. Nat. Rev. Gastroenterol. Hepatol. 12, 387–400 (2015).
Mridha, A. R. et al. NLRP3 inflammasome blockade reduces liver inflammation and fibrosis in experimental NASH in mice. J. Hepatol. 66, 1037–1046 (2017).
Bronner, D. N. et al. Endoplasmic reticulum stress activates the inflammasome via nlrp3- and caspase-2-driven mitochondrial damage. Immunity 43, 451–462 (2015).
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).
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).
Schuster, S., Cabrera, D., Arrese, M. & Feldstein, A. E. Triggering and resolution of inflammation in NASH. Nat. Rev. Gastroenterol. Hepatol. 15, 349–364 (2018).
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).
Wree, A. et al. NLRP3 inflammasome activation results in hepatocyte pyroptosis, liver inflammation, and fibrosis in mice. Hepatology 59, 898–910 (2014).
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).
Gaul, S. et al. Hepatocyte pyroptosis and release of inflammasome particles induce stellate cell activation and liver fibrosis. J. Hepatol. 74, 156–167 (2021).
Gan, C., Cai, Q., Tang, C. & Gao, J. Inflammasomes and pyroptosis of liver cells in liver fibrosis. Front. Immunol. 13, 896473 (2022).
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).
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).
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).
Fromenty, B. & Roden, M. Mitochondrial alterations in fatty liver diseases. J. Hepatol. 78, 415–429 (2022).
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).
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).
Malhotra, J. D. et al. Antioxidants reduce endoplasmic reticulum stress and improve protein secretion. Proc. Natl Acad. Sci. USA 105, 18525–18530 (2008).
Mansouri, A., Gattolliat, C.-H. & Asselah, T. Mitochondrial dysfunction and signaling in chronic liver diseases. Gastroenterology 155, 629–647 (2018).
Tu, B. P. & Weissman, J. S. Oxidative protein folding in eukaryotes. J. Cell Biol. 164, 341–346 (2004).
Sevier, C. S. & Kaiser, C. A. Ero1 and redox homeostasis in the endoplasmic reticulum. Biochim. Biophys. Acta 1783, 549–556 (2008).
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).
Flamment, M., Hajduch, E., Ferré, P. & Foufelle, F. New insights into ER stress-induced insulin resistance. Trends Endocrinol. Metab. 23, 381–390 (2012).
Chowdhry, S. et al. Loss of Nrf2 markedly exacerbates nonalcoholic steatohepatitis. Free. Radic. Biol. Med. 48, 357–371 (2010).
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).
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).
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).
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).
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).
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).
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).
Serviddio, G., Bellanti, F., Vendemiale, G. & Altomare, E. Mitochondrial dysfunction in nonalcoholic steatohepatitis. Expert. Rev. Gastroenterol. Hepatol. 5, 233–244 (2011).
Rui, L. Energy metabolism in the liver. Compr. Physiol. 4, 177–197 (2014).
Schirrmacher, V. Mitochondria at work: new insights into regulation and dysregulation of cellular energy supply and metabolism. Biomedicines 8, 526 (2020).
Pessayre, D. et al. Central role of mitochondria in drug-induced liver injury. Drug. Metab. Rev. 44, 34–87 (2012).
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).
McGarry, J. D. & Foster, D. W. Regulation of hepatic fatty acid oxidation and ketone body production. Annu. Rev. Biochem. 49, 395–420 (1980).
Zorov, D. B., Juhaszova, M. & Sollott, S. J. Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release. Physiol. Rev. 94, 909–950 (2014).
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).
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).
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).
Auten, R. L. & Davis, J. M. Oxygen toxicity and reactive oxygen species: the devil is in the details. Pediatr. Res. 66, 121–127 (2009).
Forman, H. J., Maiorino, M. & Ursini, F. Signaling functions of reactive oxygen species. Biochemistry 49, 835–842 (2010).
Dröge, W. Free radicals in the physiological control of cell function. Physiol. Rev. 82, 47–95 (2002).
Finkel, T. Signal transduction by mitochondrial oxidants. J. Biol. Chem. 287, 4434–4440 (2012).
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).
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).
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).
Franko, A. et al. Liver adapts mitochondrial function to insulin resistant and diabetic states in mice. J. Hepatol. 60, 816–823 (2014).
Pérez-Carreras, M. et al. Defective hepatic mitochondrial respiratory chain in patients with nonalcoholic steatohepatitis. Hepatology 38, 999–1007 (2003).
Cortez-Pinto, H. et al. Alterations in liver ATP homeostasis in human nonalcoholic steatohepatitis: a pilot study. JAMA 282, 1659–1664 (1999).
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).
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).
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).
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).
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).
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).
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).
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).
Kirsch, R. et al. Rodent nutritional model of non-alcoholic steatohepatitis: species, strain and sex difference studies. J. Gastroenterol. Hepatol. 18, 1272–1282 (2003).
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).
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).
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).
Zhang, Q. et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 464, 104–107 (2010).
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).
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).
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).
Koop, D. R. Oxidative and reductive metabolism by cytochrome P450 2E1. FASEB J. 6, 724–730 (1992).
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).
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).
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).
Emery, M. CYP2E1 activity before and after weight loss in morbidly obese subjects with nonalcoholic fatty liver disease. Hepatology 38, 428–435 (2003).
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).
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).
Chalasani, N. Hepatic cytochrome P450 2E1 activity in nondiabetic patients with nonalcoholic steatohepatitis. Hepatology 37, 544–550 (2003).
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).
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).
Abdelmegeed, M. A. et al. Cytochrome P450-2E1 promotes fast food-mediated hepatic fibrosis. Sci. Rep. 7, 39764 (2017).
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).
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).
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).
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).
Turrens, J. F. Mitochondrial formation of reactive oxygen species. J. Physiol. 552, 335–344 (2003).
Cadenas, E. & Davies, K. J. A. Mitochondrial free radical generation, oxidative stress, and aging. Free. Radic. Biol. Med. 29, 222–230 (2000).
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).
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).
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).
Herzig, S. & Shaw, R. J. AMPK: guardian of metabolism and mitochondrial homeostasis. Nat. Rev. Mol. Cell Biol. 19, 121–135 (2017).
Schattenberg, J. M. et al. Jnk1 but not jnk2 promotes the development of steatohepatitis in mice. Hepatology 43, 163–172 (2006).
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).
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).
Win, S. et al. Hepatic mitochondrial SAB deletion or knockdown alleviates diet‐induced metabolic syndrome, steatohepatitis, and hepatic fibrosis. Hepatology 74, 3127–3145 (2021).
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).
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).
Madrigal-Matute, J. & Cuervo, A. M. Regulation of liver metabolism by autophagy. Gastroenterology 150, 328–339 (2016).
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).
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).
Yu, Y. et al. Hepatic transferrin plays a role in systemic iron homeostasis and liver ferroptosis. Blood 136, 726–739 (2020).
Dixon, S. J. & Stockwell, B. R. The role of iron and reactive oxygen species in cell death. Nat. Chem. Biol. 10, 9–17 (2014).
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).
Ma, Z. et al. Resveratrol alleviates hepatic fibrosis in associated with decreased endoplasmic reticulum stress-mediated apoptosis and inflammation. Inflammation 45, 812–823 (2022).
Mencin, A. et al. Alpha-1 antitrypsin Z protein (PiZ) increases hepatic fibrosis in a murine model of cholestasis. Hepatology 46, 1443–1452 (2007).
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).
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).
Thomsen, M. K. et al. Lack of immunological DNA sensing in hepatocytes facilitates hepatitis B virus infection. Hepatology 64, 746–759 (2016).
Maher, J. J. Macrophages steal STING from the infectious disease playbook to promote nonalcoholic fatty liver disease. Gastroenterology 155, 1687–1688 (2018).
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).
Diamond, D. L. et al. Proteomic profiling of human liver biopsies: hepatitis C virus-induced fibrosis and mitochondrial dysfunction. Hepatology 46, 649–657 (2007).
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).
Rehman, H. et al. The mitochondria-targeted antioxidant MitoQ attenuates liver fibrosis in mice. Int. J. Physiol. Pathophysiol. Pharmacol. 8, 14–27 (2016).
Mitchell, C. et al. Protection against hepatocyte mitochondrial dysfunction delays fibrosis progression in mice. Am. J. Pathol. 175, 1929–1937 (2009).
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).
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).
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).
Shan, S. et al. Drp1-mediated mitochondrial fission promotes carbon tetrachloride-induced hepatic fibrogenesis in mice. Toxicol. Res. 11, 486–497 (2022).
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).
Scarpulla, R. C., Vega, R. B. & Kelly, D. P. Transcriptional integration of mitochondrial biogenesis. Trends Endocrinol. Metab. 23, 459–466 (2012).
Xu, J. et al. The role of human cytochrome P450 2E1 in liver inflammation and fibrosis. Hepatol. Commun. 1, 1043–1057 (2017).
Gao, J. et al. High CYP2E1 activity correlates with hepatofibrogenesis induced by nitrosamines. Oncotarget 8, 112199–112210 (2017).
Mannaerts, I. et al. Unfolded protein response is an early, non-critical event during hepatic stellate cell activation. Cell Death Dis. 10, 98 (2019).
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).
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).
Hernández-Gea, V. et al. Endoplasmic reticulum stress induces fibrogenic activity in hepatic stellate cells through autophagy. J. Hepatol. 59, 98–104 (2013).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Guimarães, E. L. et al. Mitochondrial uncouplers inhibit hepatic stellate cell activation. BMC Gastroenterol. 12, 68 (2012).
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).
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).
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).
Sancho, P. et al. NADPH oxidase NOX4 mediates stellate cell activation and hepatocyte cell death during liver fibrosis development. PLoS ONE 7, e45285 (2012).
Sasaki, Y. et al. NOX4 regulates CCR2 and CCL2 mRNA stability in alcoholic liver disease. Sci. Rep. 7, 46144 (2017).
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).
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).
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).
Thuy, L. T. T. et al. Absence of cytoglobin promotes multiple organ abnormalities in aged mice. Sci. Rep. 6, 24990 (2016).
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).
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).
Knorr, J. et al. Interleukin‐18 signaling promotes activation of hepatic stellate cells in mouse liver fibrosis. Hepatology 77, 1968–1972 (2023).
Zhao, Y. et al. p66Shc contributes to liver fibrosis through the regulation of mitochondrial reactive oxygen species. Theranostics 9, 1510–1522 (2019).
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).
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).
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).
Jia, D. et al. Pyrroloquinoline-quinone suppresses liver fibrogenesis in mice. PLoS ONE 10, e0121939 (2015).
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).
Zhou, Y. et al. Oxidative stress-mediated mitochondrial fission promotes hepatic stellate cell activation via stimulating oxidative phosphorylation. Cell Death Dis. 13, 689 (2022).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Dong, Z. et al. Adiponectin attenuates liver fibrosis by inducing nitric oxide production of hepatic stellate cells. J. Mol. Med. 93, 1327–1339 (2015).
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).
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).
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).
Horn, T., Christoffersen, P. & Henriksen, J. H. Alcoholic liver injury: defenestration in noncirrhotic livers – a scanning electron microscopic study. Hepatology 7, 77–82 (1987).
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).
DeLeve, L. D. & Maretti-Mira, A. C. Liver sinusoidal endothelial cell: an update. Semin. Liver Dis. 37, 377–387 (2017).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Wang, Q. et al. Role of XBP1 in regulating the progression of non-alcoholic steatohepatitis. J. Hepatol. 77, 312–325 (2022).
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).
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).
Nieto, N. Oxidative-stress and IL-6 mediate the fibrogenic effects of rodent Kupffer cells on stellate cells. Hepatology 44, 1487–1501 (2006).
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).
Liu, Y. et al. S100A8-mediated NLRP3 inflammasome-dependent pyroptosis in macrophages facilitates liver fibrosis progression. Cells 11, 3579 (2022).
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).
Pan, J. et al. Fatty acid activates NLRP3 inflammasomes in mouse Kupffer cells through mitochondrial DNA release. Cell. Immunol. 332, 111–120 (2018).
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).
Handa, P. et al. Iron alters macrophage polarization status and leads to steatohepatitis and fibrogenesis. J. Leukoc. Biol. 105, 1015–1026 (2019).
Kanamori, Y. et al. Iron-rich Kupffer cells exhibit phenotypic changes during the development of liver fibrosis in NASH. iScience 24, 102032 (2021).
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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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DOI: https://doi.org/10.1038/s41575-023-00832-w
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