Hepatocyte and immune cell crosstalk in non-alcoholic fatty liver disease

References

• Mitra S, De A, Chowdhury A. Epidemiology of non-alcoholic and alcoholic fatty liver diseases. Translational Gastroenterology and Hepatology [ AME Publishing Company]. 2020;5(16):16.
   PubMedGoogle Scholar
• Chitturi S, Wong VWS, Farrell G. Nonalcoholic fatty liver in Asia: firmly entrenched and rapidly gaining ground. J Gastroenterol Hepatol. 2011;26:163–172.
   PubMed Web of Science ®Google Scholar
• Speliotes EK, Yerges-Armstrong LM, Wu J, et al. Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet. 2011;7(3):e1001324.
   PubMed Web of Science ®Google Scholar
• Lozano R, Naghavi M, Foreman K, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: A systematic analysis for the global burden of disease study 2010. Lancet. 2012;380:2095–2128.
   PubMed Web of Science ®Google Scholar
• Ma C, Zhang Q, Greten TF. Nonalcoholic fatty liver disease promotes hepatocellular carcinoma through direct and indirect effects on hepatocytes. Febs J. 2018;285:752–762.
   PubMed Web of Science ®Google Scholar
• Puri P, Sanyal AJ. Nonalcoholic fatty liver disease: definitions, risk factors, and workup. Clin Liver Dis. 2012;1:99–103.
   Google Scholar
• Marra F, Lotersztajn S. Pathophysiology of NASH: perspectives for a targeted treatment. Curr Pharm Des. 2013;19:5250–5269.
   PubMed Web of Science ®Google Scholar
• Tilg H, Moschen AR, NAFL RM. D and diabetes mellitus. Nat Rev Gastroenterol Hepatol. 2017;14:32–42.
   PubMed Web of Science ®Google Scholar
• Sharma M, Mitnala S, Vishnubhotla RK, et al. The riddle of nonalcoholic fatty liver disease: progression from nonalcoholic fatty liver to nonalcoholic steatohepatitis. J Clin Exp Hepatol. 2015;5:147–158.
   PubMed Web of Science ®Google Scholar
• Horst AK, Najjar SM, Wagener C, et al. CEACAM1 in liver injury, metabolic and immune regulation. Int J Mol Sci. 2018;19:3110.
   Web of Science ®Google Scholar
• Olson NC, Doyle MF, De Boer IH, et al. Associations of circulating lymphocyte subpopulations with type 2 diabetes: cross-sectional results from the multi-ethnic study of atherosclerosis (MESA). PLoS One. 2015;10:1–14.
   Web of Science ®Google Scholar
• Buzzetti E, Pinzani M, Tsochatzis EA. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). J Metabol. 2016;65:1038–1048.
   Google Scholar
• Nati M, Haddad D, Birkenfeld AL, et al. The role of immune cells in metabolism-related liver inflammation and development of non-alcoholic steatohepatitis (NASH). Rev Endocr Metab Disord. 2016;17:29–39.
   PubMed Web of Science ®Google Scholar
• Gadd VL, Skoien R, Powell EE, et al. The portal inflammatory infiltrate and ductular reaction in human nonalcoholic fatty liver disease. Hepatology. 2014;59:1393–1405.
   PubMed Web of Science ®Google Scholar
• Tang Y, Bian Z, Zhao L, et al. Interleukin-17 exacerbates hepatic steatosis and inflammation in non-alcoholic fatty liver disease. Clin Exp Immunol. 2011;166:281–290.
   PubMed Web of Science ®Google Scholar
• Jia Q, Li C, Xia Y, et al. Association between complement C3 and prevalence of fatty liver disease in an adult population: A cross-sectional study from the Tianjin chronic low-grade systemic inflammation and health (TCLSIHealth) cohort study. PLoS One. 2015;10:1–10.
   Web of Science ®Google Scholar
• Rensen SS, Slaats Y, Driessen A, et al. Activation of the complement system in human nonalcoholic fatty liver disease. Hepatology. 2009;50:1809–1817.
   PubMed Web of Science ®Google Scholar
• Kubes P, Mehal WZ. Sterile inflammation in the liver. Gastroenterology. 2012;143:1158–1172.
   PubMed Web of Science ®Google Scholar
• Sutti S, Albano E. Adaptive immunity: an emerging player in the progression of NAFLD. Nat. Rev. Gastroenterol. Hepatology Nature Research. 2020;17:81–92.
   PubMed Web of Science ®Google Scholar
• Sima P, Vannucci L, Vetvicka V. Atherosclerosis as autoimmune disease. Ann Transl Med. 2018;6:116.
   PubMed Web of Science ®Google Scholar
• Ilan Y. Compounds of the sphingomyelin-ceramide-glycosphingolipid pathways as secondary messenger molecules: new targets for novel therapies for fatty liver disease and insulin resistance. Am J Physiol Gastrointest Liver Physiol. 2016;310:G1102–17.
   PubMed Web of Science ®Google Scholar
• Arrese M, Cabrera D, Kalergis AM, et al. Innate immunity and inflammation in NAFLD/NASH. Dig Dis Sci. 2016;61:1294–1303.
   PubMed Web of Science ®Google Scholar
• Chen GY, Nuñez G. Sterile inflammation: sensing and reacting to damage. Nat Rev Immunol. 2010;10:826–837.
   PubMed Web of Science ®Google Scholar
• Ganz M, Bukong TN, Csak T, et al. Progression of non-alcoholic steatosis to steatohepatitis and fibrosis parallels cumulative accumulation of danger signals that promote inflammation and liver tumors in a high fat-cholesterol-sugar diet model in mice. J Transl Med. 2015;13:1–14.
   PubMed Web of Science ®Google Scholar
• Handa P, Vemulakonda A, Kowdley KV, et al. Mitochondrial DNA from hepatocytes as a ligand for TLR9: drivers of nonalcoholic steatohepatitis? World J Gastroenterol. 2016;22:6965–6971.
   PubMed Web of Science ®Google Scholar
• Guo H, Callaway JB, Ting JPY. Inflammasomes: mechanism of action, role in disease and therapeutics. Nat Med. 2015;21:677–687.
   PubMed Web of Science ®Google Scholar
• Cha J, Kim D, Chun K. The role of hepatic macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Lab Anim Res. 2018;34:133–139.
   Google Scholar
• Swanson KV, Deng M, Ting JPY. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat Rev Immunol. 2019;19:477–489.
   PubMed Web of Science ®Google Scholar
• Brenner C, Galluzzi L, Kepp O, et al. Decoding cell death signals in liver inflammation. J Hepatol. 2013;59:583–594.
   PubMed Web of Science ®Google Scholar
• Engin A. What is Lipotoxicity? In: Engin AB, Engin A, editors. Obesity and Lipotoxicity: adv. Exp. Med. Biol. Switzerland (CH): Springer International Publishing; 2017. p. 198–199.
   Google Scholar
• Gastaldelli A, From CK. NASH to diabetes and from diabetes to NASH: mechanisms and treatment options. JHEP Rep. 2019;1:312–328.
   PubMedGoogle Scholar
• Farrell GC, Van Rooyen D, Gan L, et al. NASH is an inflammatory disorder: pathogenic, prognostic and therapeutic implications. Gut Liver. 2012;6:149–171.
   PubMed Web of Science ®Google Scholar
• Li ZZ, Berk M, McIntyre TM, et al. The lysosomal-mitochondrial axis in free fatty acid-induced hepatic lipotoxicity. Hepatology. 2008;47:1495–1503.
   PubMed Web of Science ®Google Scholar
• Chatterjee S, Ganini D, Tokar EJ, et al. Leptin is key to peroxynitrite-mediated oxidative stress and Kupffer cell activation in experimental non-alcoholic steatohepatitis. J Hepatol. 2012;58:778–784.
   PubMed Web of Science ®Google Scholar
• Chen GY, Tang J, Zheng P, et al. CD24 and siglec-10 selectively repress tissue damage-induced immune responses. Science. 2009;323:1722–1725.
   PubMed Web of Science ®Google Scholar
• Tang T, Sui Y, Lian M, et al. Pro-inflammatory activated Kupffer cells by lipids induce hepatic NKT cells deficiency through activation-induced cell death. PLoS One. 2012;8:1–11.
   Web of Science ®Google Scholar
• Abdullah Z, Knolle PA. Liver macrophages in healthy and diseased liver. Pflugers Arch Eur J Physiol. 2017;469:553–560.
   PubMed Web of Science ®Google Scholar
• Smedsrod B, Bleser D, Braet F, et al. Cell biology of liver endothelial and Kupffer cells. Gut. 1994;35:1509–1516.
   PubMed Web of Science ®Google Scholar
• Kempka G, Victoria K-B. Binding, uptake, and transcytosis of ligands for receptors in rat liver: an electron microscopic study. Exp Cell Res. 1998;176:38–48.
   Google Scholar
• Cheong H, Lee SS, Lee JS, et al. Phagocytic function of Kupffer cells in mouse nonalcoholic fatty liver disease models: evaluation with superparamagnetic iron oxide MRI. J Magn Reson Imaging. 2015;41:1218–1227.
   PubMed Web of Science ®Google Scholar
• Asanuma T, Ono M, Kubota K, et al. Super paramagnetic iron oxide MRI shows defective Kupffer cell uptake function in non-alcoholic fatty liver disease. Gut. 2010;59:258–266.
   PubMed Web of Science ®Google Scholar
• Zhan YT, An W. Roles of liver innate immune cells in nonalcoholic fatty liver disease. World J Gastroenterol. 2010;16:4652–4660.
   PubMed Web of Science ®Google Scholar
• Wan J, Benkdane M, Teixeira-Clerc F, et al. M2 Kupffer cells promote M1 Kupffer cell apoptosis: a protective mechanism against alcoholic and nonalcoholic fatty liver disease. Hepatology. 2014;59:130–142.
   PubMed Web of Science ®Google Scholar
• Leroux A, Ferrere G, Godie V, et al. Toxic lipids stored by Kupffer cells correlates with their pro-inflammatory phenotype at an early stage of steatohepatitis. J Hepatol. 2012;57:141–149.
   PubMed Web of Science ®Google Scholar
• Gao B, Il JW, Liver TZ. An organ with predominant innate immunity. Hepatology. 2008;47:729–736.
   PubMed Web of Science ®Google Scholar
• Cai J, Zhang X, Li H. The role of innate immune cells in nonalcoholic steatohepatitis. Hepatology. 2019;70:1026–1037.
   PubMedGoogle Scholar
• Beuers U, Gershwin ME. Unmet challenges in immune-mediated hepatobiliary diseases. Clin Rev Allergy Immunol. 2015;48:127–131.
   PubMed Web of Science ®Google Scholar
• Locatelli I, Sutti S, Vacchiano M, et al. NF-κB1 deficiency stimulates the progression of non-alcoholic steatohepatitis (NASH) in mice by promoting NKT-cell-mediated responses. Clin Sci. 2013;124:279–287.
   PubMed Web of Science ®Google Scholar
• Rivera CA, Adegboyega P, van Rooijen N, et al. Toll-like receptor-4 signaling and Kupffer cells play pivotal roles in the pathogenesis of non-alcoholic steatohepatitis. J Hepatol. 2007;47:571–579.
   PubMed Web of Science ®Google Scholar
• Miura K, Kodama Y, Inokuchi S, et al. Toll-like receptor 9 promotes steatohepatitis by induction of interleukin-1β in mice. Gastroenterology. 2010;139:323–334.
   PubMed Web of Science ®Google Scholar
• Meli R, Raso GM, Calignano A. Role of innate immune response in non-alcoholic fatty liver disease: metabolic complications and therapeutic tools. Front Immunol. 2014;5:1–14.
   PubMed Web of Science ®Google Scholar
• Lanthier N, Molendi-Coste O, Cani PD, et al. Kupffer cell depletion prevents but has no therapeutic effect on metabolic and inflammatory changes induced by a high-fat diet. Faseb J. 2011;25:4301–4311.
   PubMed Web of Science ®Google Scholar
• Bhattacharjee J, Kirby M, Softic S, et al. Hepatic natural killer T-cell and CD8+ T-cell signatures in mice with nonalcoholic steatohepatitis. Hepatol Commun. 2017;1:299–310.
   PubMed Web of Science ®Google Scholar
• Wolf MJ, Adili A, Piotrowitz K, et al. Metabolic activation of intrahepatic CD8+ T cells and NKT cells causes nonalcoholic steatohepatitis and liver cancer via cross-talk with hepatocytes. Cancer Cell. 2014;26:549–564.
   PubMed Web of Science ®Google Scholar
• Nishimura S, Manabe I, Nagasaki M, et al. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat Med. 2009;15:914–920.
   PubMed Web of Science ®Google Scholar
• Van, Herck MA, Weyler J, et al. The differential roles of T-cells in non-alcoholic fatty liver disease and obesity. Front Immunol. 2019;10:82.
   PubMed Web of Science ®Google Scholar
• Rajoriya N, Fergusson JR, Leithead JA, et al. Gamma delta T-lymphocytes in hepatitis C and chronic liver disease. Front Immunol. 2014;5:1–9.
   PubMed Web of Science ®Google Scholar
• Giles D, Moreno-Fernandez M, Divanovic SIL. 17 axis driven inflammation in non-alcoholic fatty liver disease progression. Curr Drug Targets. 2015;16:1315–1323.
   PubMed Web of Science ®Google Scholar
• Harley ITW, Stankiewicz TE, Giles DA, et al. IL-17 signaling accelerates the progression of nonalcoholic fatty liver disease in mice. Hepatology. 2014;59:1830–1839.
   PubMed Web of Science ®Google Scholar
• Xu R, Tao A, Zhang S, et al. Neutralization of interleukin-17 attenuates high fat diet-induced non-alcoholic fatty liver disease in mice. Acta Biochim Biophys Sin. 2013;45:726–733.
   Google Scholar
• Fabre T, Kared H, Friedman SL, et al. IL-17A enhances the expression of profibrotic genes through upregulation of the TGF-β receptor on hepatic stellate cells in a JNK-dependent manner. J Immunol. 2014;193:3925–3933.
   PubMed Web of Science ®Google Scholar
• Li F, Hao X, Chen Y, et al. The microbiota maintain homeostasis of liver-resident γδT-17 cells in a lipid antigen/CD1d-dependent manner. Nat Commun. 2017;8:13839.
   Web of Science ®Google Scholar
• He B, Wu L, Xie W, et al. The imbalance of Th17/Treg cells is involved in the progression of nonalcoholic fatty liver disease in mice. BMC Immunol. 2017;18:33.
   PubMed Web of Science ®Google Scholar
• Maggio R, Viscomi C, Andreozzi P, et al. Normocaloric low cholesterol diet modulates Th17/Treg balance in patients with chronic hepatitis C virus infection. PLoS One. 2014;9:e112346.
   PubMed Web of Science ®Google Scholar
• Ma X, Hua J, Mohamood AR, et al. A high-fat diet and regulatory T cells influence susceptibility to endotoxin-induced liver injury. Hepatology. 2007;46:1519–1529.
   PubMed Web of Science ®Google Scholar
• Rau M, Schilling A-K, Meertens J, et al. Progression from nonalcoholic fatty liver to nonalcoholic steatohepatitis is marked by a higher frequency of Th17 Cells in the liver and an increased Th17/resting regulatory T Cell ratio in peripheral blood and in the liver. J Immunol. 2016;196:97–105.
   PubMed Web of Science ®Google Scholar
• Vasseur P, Dion S, Filliol A, et al. Endogenous IL-33 has no effect on the progression of fibrosis during experimental steatohepatitis. Oncotarget. 2017;8:48563–48574.
   PubMedGoogle Scholar
• Zhang X, Jin J, Peng X, et al. Simvastatin inhibits IL-17 secretion by targeting multiple IL-17-regulatory cytokines and by inhibiting the expression of IL-17 transcription factor RORC in CD4+ lymphocytes. J Immunol. 2008;180:6988–6996.
   PubMed Web of Science ®Google Scholar
• Byun J-S, Yi H-S. Hepatic immune microenvironment in alcoholic and nonalcoholic liver disease. Biomed Res Int. 2017;6862439:2017.
   Google Scholar
• Wang X, Tian Z γδ T cells in liver diseases. Front. Med. Higher Education Press. 12, 262–268 (2018).
   Google Scholar
• Schuster S, Cabrera D, Arrese M, et al. Triggering and resolution of inflammation in NASH. Nat Rev Gastroenterol Hepatol. 2018;15:349–364.
   PubMed Web of Science ®Google Scholar
• Gaens KHJ, Niessen PMG, Rensen SS, et al. Endogenous formation of Nε-(carboxymethyl) lysine is increased in fatty livers and induces inflammatory markers in an in vitro model of hepatic steatosis. J Hepatol. 2012;56:647–655.
   PubMed Web of Science ®Google Scholar
• Macek Jilkova Z, Afzal S, Marche H, et al. Progression of fibrosis in patients with chronic viral hepatitis is associated with IL-17(+) neutrophils. Liver Int. 2016;36:1116–1124.
   PubMed Web of Science ®Google Scholar
• Margetts J, Ogle LF, Chan SL, et al. Neutrophils: driving progression and poor prognosis in hepatocellular carcinoma? Br J Cancer. 2018;118:248–257.
   PubMed Web of Science ®Google Scholar
• Brinkmann V, Reichard U, Goosmann C, et al. Neutrophil extracellular traps kill bacteria. Science. 2004;303:1532–1535.
   PubMed Web of Science ®Google Scholar
• Papayannopoulos V. Neutrophil extracellular traps in immunity and disease. Nat Rev Immunol. 2018;18:134–147.
   PubMed Web of Science ®Google Scholar
• van der Windt DJ, Sud V, Zhang H, et al. Neutrophil extracellular traps promote inflammation and development of hepatocellular carcinoma in nonalcoholic steatohepatitis. Hepatology. 2018;68:1347–1360.
   PubMed Web of Science ®Google Scholar
• Hilscher MB, Sehrawat T, Arab JP, et al. Mechanical stretch increases expression of cxcl1 in liver sinusoidal endothelial cells to recruit neutrophils, generate sinusoidal microthombi, and promote portal hypertension. Gastroenterology. 2019;157:193–209.
   PubMed Web of Science ®Google Scholar
• Berzins SP, Smyth MJ, Baxter AG. Presumed guilty: natural killer T cell defects and human disease. Nat Rev Immunol. 2011;11:131–142.
   PubMed Web of Science ®Google Scholar
• Swain MG. Natural killer T cells within the liver: conductors of the hepatic immune orchestra. Dig Dis. 2010;28:7–13.
   PubMed Web of Science ®Google Scholar
• Cepero-Donates Y, Rakotoarivelo V, Mayhue M, et al. Homeostasis of IL-15 dependent lymphocyte subsets in the liver. Cytokine. 2016;82:95–101.
   PubMed Web of Science ®Google Scholar
• Adler M, Taylor S, Okebugwu K, et al. Intrahepatic natural killer t cell populations are increased in human hepatic steatosis. World J Gastroenterol. 2011;17:1725–1731.
   PubMed Web of Science ®Google Scholar
• Tajiri K, Shimizu Y. Role of NKT cells in the pathogenesis of NAFLD. Int J Hepatol. 2012;1–6:2012.
   Google Scholar
• Tang Z-H, Liang S, Potter J, et al. Tim-3/galectin-9 regulate the homeostasis of hepatic NKT cells in a murine model of nonalcoholic fatty liver disease. J Immunol. 2013;190:1788–1796.
   PubMed Web of Science ®Google Scholar
• Durante-Mangoni E, Wang R, Shaulov A, et al. Hepatic CD1d expression in hepatitis C virus infection and recognition by resident proinflammatory CD1d-reactive T cells. J Immunol. 2004;173:2159–2166.
   PubMed Web of Science ®Google Scholar
• Kumar V. NKT-cell subsets: promoters and protectors in inflammatory liver disease. J Hepatol. 2013;59:618–620.
   PubMed Web of Science ®Google Scholar
• Liang S, Webb T, Li Z. Probiotic antigens stimulate hepatic natural killer T cells. Immunology. 2014;141:203–210.
   PubMed Web of Science ®Google Scholar
• Guo J, Friedman SL. Toll-like receptor 4 signaling in liver injury and hepatic fibrogenesis. Fibrogenes Tissue Repair. 2010;3:21.
   PubMedGoogle Scholar
• B V M-M, You Q, Wang H, et al. Mice lacking natural killer T cells are more susceptible to metabolic alterations following high fat diet feeding. PLoS One. 2014;9:e80949.
   PubMed Web of Science ®Google Scholar
• Syn W-K, Agboola KM, Swiderska M, et al. NKT-associated hedgehog and osteopontin drive fibrogenesis in non-alcoholic fatty liver disease. Gut. 2012;61:1323–1329.
   PubMed Web of Science ®Google Scholar
• Syn W-K, Oo YH, Pereira TA, et al. Accumulation of natural killer T cells in progressive nonalcoholic fatty liver disease. Hepatology. 2010;51:1998–2007.
   PubMed Web of Science ®Google Scholar
• Malhi H, Bronk SF, Werneburg NW, et al. Free fatty acids induce JNK-dependent hepatocyte lipoapoptosis. J Biol Chem. 2006;281:12093–12101.
   PubMed Web of Science ®Google Scholar
• Kremer M, Thomas E, Milton RJ, et al. Kupffer cell and interleukin-12-dependent loss of natural killer T cells in hepatosteatosis. Hepatology. 2010;51:130–141.
   PubMed Web of Science ®Google Scholar
• Xu C-F, Yu C-H, Li Y-M, et al. Association of the frequency of peripheral natural killer T cells with nonalcoholic fatty liver disease. World J Gastroenterol. 2007;13:4504–4508.
   PubMed Web of Science ®Google Scholar
• Kremer M, Hines IN. Natural killer T cells and non-alcoholic fatty liver disease: fat chews on the immune system. World J Gastroenterol. 2008;14:487–488.
   PubMed Web of Science ®Google Scholar
• Hua J, Ma X, Webb T, et al. Dietary fatty acids modulate antigen presentation to hepatic NKT cells in nonalcoholic fatty liver disease. J Lipid Res. 2010;51:1696–1703.
   PubMed Web of Science ®Google Scholar
• Lamas O, Martínez JA, Marti A. Energy restriction restores the impaired immune response in overweight (cafeteria) rats. J Nutr Biochem. 2004;15:418–425.
   PubMed Web of Science ®Google Scholar
• O’Shea D, Cawood TJ, O’Farrelly C, et al. Natural killer cells in obesity: impaired function and increased susceptibility to the effects of cigarette smoke. PLoS One. 2010;5:e8660.
   PubMed Web of Science ®Google Scholar
• Kahraman A, Gerken G, Canbay A. Apoptosis in immune-mediated liver diseases. Dig Dis. 2010;28:144–149.
   PubMed Web of Science ®Google Scholar
• Shi FD, Ljunggren HG, La Cava A, et al. Organ-specific features of natural killer cells. Nat Rev Immunol. 2011;11:658–671.
   PubMed Web of Science ®Google Scholar
• Radaeva S, Sun R, Jaruga B, et al. Natural killer cells ameliorate liver fibrosis by killing activated stellate cells in NKG2D-dependent and tumor necrosis factor-related apoptosis-inducing ligand-dependent manners. Gastroenterology. 2006;130:435–452.
   PubMed Web of Science ®Google Scholar
• Feldstein AE, Canbay A, Angulo P, et al. Hepatocyte apoptosis and Fas expression are prominent features of human nonalcoholic steatohepatitis. Gastroenterology. 2003;125:437–443.
   PubMed Web of Science ®Google Scholar
• Xia C, Rao X, Zhong J. Role of T lymphocytes in type 2 Diabetes and Diabetes-associated inflammation. J Diabetes Res. 2017;6494795:1–6.
   Google Scholar
• Lee BC, Kim MS, Pae M, et al. Adipose natural killer cells regulate adipose tissue macrophages to promote insulin resistance in obesity. Cell Metab. 2016;23:685–698.
   PubMed Web of Science ®Google Scholar
• Farrell GC, Haczeyni F, Chitturi S. Pathogenesis of NASH: how metabolic complications of overnutrition favour lipotoxicity and pro-inflammatory fatty liver disease. Adv Exp Med Biol. 2018;1061:19–44.
   PubMed Web of Science ®Google Scholar
• Lackner C, Gogg-Kamerer M, Zatloukal K, et al. Ballooned hepatocytes in steatohepatitis: the value of keratin immunohistochemistry for diagnosis. J Hepatol. 2008;48:821–828.
   PubMed Web of Science ®Google Scholar
• Hirsova P, Gores GJ. Death receptor-mediated cell death and proinflammatory signaling in nonalcoholic steatohepatitis. Cell Mol Gastroenterol Hepatol. 2015;1:17–27.
   PubMed Web of Science ®Google Scholar
• Kayaçetin S, Başaranoʇlu M. Mallory-Denk bodies: correlation with steatosis, severity, zonal distribution, and identification with ubiquitin. Turkish J Gastroenterol. 2015;26:506–510.
   PubMed Web of Science ®Google Scholar
• Strnad P, Zatloukal K, Stumptner C, et al. Mallory-Denk-bodies: lessons from keratin-containing hepatic inclusion bodies. Biochim Biophys Acta - Mol Basis Dis. 1782;764–74:2008.
   Google Scholar
• French BA, Oliva J, Bardag-Gorce F, et al. The immunoproteasome in steatohepatitis: its role in Mallory-Denk body formation. Exp Mol Pathol. 2011;90:252–256.
   PubMed Web of Science ®Google Scholar
• Kimura H, Caturegli P, Takahashi M, et al. New insights into the function of the immunoproteasome in immune and nonimmune Cells. J Immunol Res. 2015;8:541984.
   Google Scholar
• Matteoni CA, Younossi ZM, Gramlich T, et al. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology. 1999;116:1413–1419.
   PubMed Web of Science ®Google Scholar
• Estep M, Mehta R, Bratthauer G, et al. Hepatic sonic hedgehog protein expression measured by computer assisted morphometry significantly correlates with features of non-alcoholic steatohepatitis. BMC Gastroenterol. 2019;19:1–7.
   PubMed Web of Science ®Google Scholar
• Richardson MM, Jonsson JR, Powell EE, et al. Progressive fibrosis in nonalcoholic steatohepatitis: association with altered regeneration and a ductular reaction. Gastroenterology. 2007;133:80–90.
   PubMed Web of Science ®Google Scholar
• Caldwell S, Yoshihiro I. Hepatocellular ballooning in NASH. J Hepatol. 2010;53:564–574.
   Web of Science ®Google Scholar
• Kakisaka K, Cazanave SCA. Hedgehog survival pathway in ‘undead’ lipotoxic hepatocytes. J Hepatol. 2012;87:844–851.
   Google Scholar
• S V F, Choi SS, Yang L, et al. Hepatic accumulation of hedgehog-reactive progenitors increases with severity of fatty liver damage in mice. Lab Invest. 2007;87:1227–1239.
   PubMed Web of Science ®Google Scholar
• Syn W-K, Choi SS, Liaskou E, et al. Osteopontin is induced by hedgehog pathway activation and promotes fibrosis progression in nonalcoholic steatohepatitis. Hepatology. 2011;53:106–115.
   PubMed Web of Science ®Google Scholar
• Nagoshi S. Osteopontin: versatile modulator of liver diseases. Hepatol Res. 2014;44:22–30.
   PubMed Web of Science ®Google Scholar
• Hirsova P, GJ G. Hedgehog and vitamin E: therapeutic implications. Hepatology. 2015;61:15–17.
   PubMed Web of Science ®Google Scholar
• Verdelho Machado M, Diehl AM. The hedgehog pathway in nonalcoholic fatty liver disease. Crit Rev Biochem Mol Biol. 2018;53:264–278.
   PubMed Web of Science ®Google Scholar
• Marra F, Svegliati-Baroni G. Lipotoxicity and the gut-liver axis in NASH pathogenesis. J Hepatol. 2018;68:280–295.
   PubMed Web of Science ®Google Scholar
• Feldstein AE, Gores GJ. Apoptosis in alcoholic and nonalcoholic steatohepatitis. Gastroenterology. 2005;10:3093–3099.
   Google Scholar
• Galluzzi L, Vitale I, Aaronson SA, et al. Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. Cell Death Differ. 2018;25:486–541.
   PubMed Web of Science ®Google Scholar
• Kalkavan H, Green DR. MOMP, cell suicide as a BCL-2 family business. Cell Death Differ. 2018;25:46–55.
   PubMed Web of Science ®Google Scholar
• Shalini S, Dorstyn L, Dawar S, et al. Old, new and emerging functions of caspases. Cell Death Differ. 2015;22:526–539.
   PubMed Web of Science ®Google Scholar
• Akazawa Y, Nakao K. To die or not to die: death signaling in nonalcoholic fatty liver disease. J Gastroenterol. 2018;53:893–906.
   PubMed Web of Science ®Google Scholar
• McPartland JL, Guzail MA, Kendall CH, et al. Apoptosis in chronic viral hepatitis parallels histological activity: an immunohistochemical investigation using anti-activated caspase-3 and M30 cytodeath antibody. Int J Exp Pathol. 2005;86:19–24.
   PubMed Web of Science ®Google Scholar
• Canbakan B, Senturk H, Canbakan M, et al. Reliability of caspase activity as a biomarker of hepatic apoptosis in nonalcoholic fatty liver disease. Biomarker Med. 2011;5:813–815.
   PubMed Web of Science ®Google Scholar
• Thapaliya S, Wree A, Povero D, et al. Caspase 3 inactivation protects against hepatic cell death and ameliorates fibrogenesis in a diet-induced NASH model. Dig Dis Sci. 2014;59:1197–1206.
   PubMed Web of Science ®Google Scholar
• Wieckowska A, Zein NN, Yerian LM, et al. In vivo assessment of liver cell apoptosis as a novel biomarker of disease severity in nonalcoholic fatty liver disease. Hepatology. 2006;44:27–33.
   PubMed Web of Science ®Google Scholar
• Elalfy H, Besheer T, Elhammady D, et al. Model for non-invasive diagnosis of NAFLD incorporating caspase 3-cleaved cytokeratin-18: a clinical, serological, and immunohistochemical analysis. Hepat Mon. 2018;18:e60168.
   Web of Science ®Google Scholar
• Shen X, Guo H, Xu J, et al. Inhibition of lncRNA HULC improves hepatic fibrosis and hepatocyte apoptosis by inhibiting the MAPK signaling pathway in rats with nonalcoholic fatty liver disease. J Cell Physiol. 2019;234:18169–18179.
   PubMed Web of Science ®Google Scholar
• Alt Y, Grimm A, Schlegel L, et al. The impact of liver cell injury on health related quality of life in patients with chronic liver disease. PLoS One. 2016;11:1–12.
   Google Scholar
• Aizawa S, Brar G, Tsukamoto H. Cell death and liver disease. Gut Liver. 2019;14:20–29.
   Web of Science ®Google Scholar
• Newton K, Manning G. Necroptosis and inflammation. Annu Rev Biochem. 2016;85:743–763.
   PubMed Web of Science ®Google Scholar
• Pasparakis M, Vandenabeele P. Necroptosis and its role in inflammation. Nature. 2015;517:311–320.
   PubMed Web of Science ®Google Scholar
• Afonso MB, Rodrigues PM, Carvalho T, et al. Necroptosis is a key pathogenic event in human and experimental murine models of non-alcoholic steatohepatitis. Clin Sci. 2015;129:721–739.
   Web of Science ®Google Scholar
• Liedtke C, Bangen JM, Freimuth J, et al. Loss of caspase-8 protects mice against inflammation-related hepatocarcinogenesis but induces non-apoptotic liver injury. Gastroenterology. 2011;141:2176–2187.
   PubMed Web of Science ®Google Scholar
• Tsurusaki S, Tsuchiya Y, Koumura T, et al. Hepatic ferroptosis plays an important role as the trigger for initiating inflammation in nonalcoholic steatohepatitis. Cell Death Dis. 2019;10:449.
   PubMed Web of Science ®Google Scholar
• Ramos-Junior ES, Morandini AC. Gasdermin: A new player to the inflammasome game. Biomed J. 2017;40:313–316.
   PubMed Web of Science ®Google Scholar
• McIlwain DR, Berger T, Mak TW. Caspase functions in cell death and disease. Cold Spring Harb Perspect Biol. 2013;5:1–28.
   Web of Science ®Google Scholar
• Guo H, Xie M, Zhou C, et al. The relevance of pyroptosis in the pathogenesis of liver diseases. Life Sci. 2019;223:69–73.
   PubMed Web of Science ®Google Scholar
• Shi J, Gao W, Pyroptosis SF. Gasdermin-mediated programmed necrotic cell death. Trends Biochem Sci. 2017;42:245–254.
   PubMed Web of Science ®Google Scholar
• Beier JI, Banales JM. Pyroptosis: an inflammatory link between NAFLD and NASH with potential therapeutic implications. J Hepatol. 2018;68:643–645.
   PubMed Web of Science ®Google Scholar
• Khanova E, Wu R, Wang W, et al. Pyroptosis by caspase11/4-gasdermin-D pathway in alcoholic hepatitis in mice and patients. Hepatology. 2018;67:1737–1753.
   PubMed Web of Science ®Google Scholar
• Xu B, Jiang M, Chu Y, et al. Gasdermin D plays a key role as a pyroptosis executor of non-alcoholic steatohepatitis in humans and mice. J Hepatol. 2018;68:773–782.
   PubMed Web of Science ®Google Scholar
• Wree A, Eguchi A, Mcgeough MD, et al. NLRP3 inflammasome activation results in hepatocyte pyroptosis, liver inflammation, and fibrosis in mice. Hepatology. 2014;59:898–910.
   PubMed Web of Science ®Google Scholar
• Tarantino G, Citro V, Capone D. nonalcoholic fatty liver disease: a challenge from mechanisms to therapy. J Clin Med. 2019;9(15):10.3390/jcm9010015.
   PubMedGoogle Scholar
• Fontana J, Zima M, Vetvicka V. Biological markers of oxidative stress in cardiovascular diseases: after so many studies, what do we know?. Immunol Invest. 2018;47:823–843.
   PubMed Web of Science ®Google Scholar
• Vetvicka V, Garcia-Mina J, Proctor M, et al. Synergistic effects of humic acid and glucan in hepatoprotection against experimental liver injury. Austin J of Clin Pathol. 2014;1:1–4.
   Google Scholar
• McPherson S, Hardy T, Henderson E, et al. Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical management. J Hepatol. 2015;62:1148–1155.
   PubMed Web of Science ®Google Scholar
• Hamaguchi M, Kojima T, Itoh Y, et al. The severity of ultrasonographic findings in nonalcoholic fatty liver disease reflects the metabolic syndrome and visceral fat accumulation. Am J Gastroenterol. 2007;102:2708–2715.
   PubMed Web of Science ®Google Scholar