A subset of patients with non-alcoholic fatty liver disease develop an inflammatory condition, termed non-alcoholic steatohepatitis (NASH). NASH is characterised by hepatocellular injury, innate immune cell-mediated inflammation and progressive liver fibrosis. The mechanisms whereby hepatic inflammation occurs in NASH remain incompletely understood, but appear to be linked to the proinflammatory microenvironment created by toxic lipid-induced hepatocyte injury, termed lipotoxicity. In this review, we discuss the signalling pathways induced by sublethal hepatocyte lipid overload that contribute to the pathogenesis of NASH. Furthermore, we will review the role of proinflammatory, proangiogenic and profibrotic hepatocyte-derived extracellular vesicles as disease biomarkers and pathogenic mediators during lipotoxicity. We also review the potential therapeutic strategies to block the feed-forward loop between sublethal hepatocyte injury and liver inflammation.

Department of Pharmacology Faculty of Medicine Charles University Hradec Kralove Czech Republic

Division of Gastroenterology and Hepatology Mayo Clinic Rochester Minnesota USA

Division of Pediatrics Gastroenterology and Hepatology Mayo Clinic Rochester Minnesota USA

Institute of Clinical Biochemistry and Diagnostics University Hospital Hradec Kralove Hradec Kralove Czech Republic

Zobrazit více v PubMed

Younossi ZM, Koenig AB, Abdelatif D, et al. Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64:73–84. PubMed

Machado MV, Diehl AM. Pathogenesis of Nonalcoholic Steatohepatitis. Gastroenterology. 2016;150:1769–77. PubMed PMC

Arab JP, Karpen SJ, Dawson PA, et al. Bile acids and nonalcoholic fatty liver disease: molecular insights and therapeutic perspectives. Hepatology. 2017;65:350–62. PubMed PMC

Ahmed A, Wong RJ, Harrison SA. Nonalcoholic fatty liver disease review: diagnosis, treatment, and outcomes. Clin Gastroenterol Hepatol. 2015;13:2062–70. PubMed

Bonci E, Chiesa C, Versacci P, et al. Association of nonalcoholic fatty liver disease with subclinical cardiovascular changes: a systematic review and meta-analysis. Biomed Res Int. 2015;2015:1–11. PubMed PMC

Rinella ME. Nonalcoholic fatty liver disease: a systematic review. JAMA. 2015;313:2263–73. PubMed

Hirsova P, Gores GJ. Death receptor-mediated cell death and proinflammatory signaling in nonalcoholic steatohepatitis. Cell Mol Gastroenterol Hepatol. 2015;1:17–27. PubMed PMC

Bechmann LP, Gieseler RK, Sowa JP, et al. Apoptosis is associated with CD36/fatty acid translocase upregulation in non-alcoholic steatohepatitis. Liver Int. 2010;30:850–9. PubMed

Hirsova P, Ibrahim SH, Gores GJ, et al. Lipotoxic lethal and sublethal stress signaling in hepatocytes: relevance to NASH pathogenesis. J Lipid Res. 2016;57:1758–70. PubMed PMC

Hirsova P, Ibrahim SH, Malhi H, et al. Hepatocyte lethal and nonlethal lipotoxic injury. In: Ding WX, Yin XM, editors. Cellular injury in liver diseases. 1. Springer International Publishing; 2017.

Hirsova P, Ibrahim SH, Krishnan A, et al. Lipid-induced signaling causes release of inflammatory extracellular vesicles from hepatocytes. Gastroenterology. 2016;150:956–67. PubMed PMC

Ibrahim SH, Hirsova P, Tomita K, et al. Mixed lineage kinase 3 mediates release of C-X-C motif ligand 10-bearing chemotactic extracellular vesicles from lipotoxic hepatocytes. Hepatology. 2016;63:731–44. PubMed PMC

Kakazu E, Mauer AS, Yin M, et al. Hepatocytes release ceramide-enriched proinflammatory extracellular vesicles in an IRE1α-dependent manner. J Lipid Res. 2016;57:233–45. PubMed PMC

Hirsova P, Weng P, Salim W, et al. TRAIL deletion prevents liver, but not adipose tissue, inflammation during murine diet-induced obesity. Hepatol Commun. 2017;1:648–62. PubMed PMC

Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41:1313–21. PubMed

Hirsova P, Gores GJ. Ballooned hepatocytes, undead cells, sonic hedgehog, and vitamin E: therapeutic implications for nonalcoholic steatohepatitis. Hepatology. 2015;61:15–17. PubMed PMC

Rangwala F, Guy CD, Lu J, et al. Increased production of sonic hedgehog by ballooned hepatocytes. J Pathol. 2011;224:401–10. PubMed PMC

Machado MV, Diehl AM. Hedgehog signalling in liver pathophysiology. J Hepatol. 2017 PubMed PMC

Fuchs Y, Steller H. Programmed cell death in animal development and disease. Cell. 2011;147:742–58. PubMed PMC

Kakisaka K, Cazanave SC, Werneburg NW, et al. A hedgehog survival pathway in ’undead’ lipotoxic hepatocytes. J Hepatol. 2012;57:844–51. PubMed PMC

Hirsova P, Ibrahim SH, Bronk SF, et al. Vismodegib suppresses TRAIL-mediated liver injury in a mouse model of nonalcoholic steatohepatitis. PLoS One. 2013;8:e70599. PubMed PMC

Kwon H, Song K, Han C, et al. Inhibition of hedgehog signaling ameliorates hepatic inflammation in mice with nonalcoholic fatty liver disease. Hepatology. 2016;63 PubMed PMC

Guy CD, Suzuki A, Zdanowicz M, et al. Hedgehog pathway activation parallels histologic severity of injury and fibrosis in human nonalcoholic fatty liver disease. Hepatology. 2012;55:1711–21. PubMed PMC

Stumptner C, Fuchsbichler A, Heid H, et al. Mallory body-a disease-associated type of sequestosome. Hepatology. 2002;35:1053–62. PubMed

Park HW, Park H, Semple IA, et al. Pharmacological correction of obesity-induced autophagy arrest using calcium channel blockers. Nat Commun. 2014;5:4834. PubMed PMC

Umemura A, He F, Taniguchi K, et al. p62, Upregulated during preneoplasia, induces hepatocellular carcinogenesis by maintaining survival of stressed HCC-initiating cells. Cancer Cell. 2016;29:935–48. PubMed PMC

Mittal S, Bjørnevik K, Im DS, et al. β2-Adrenoreceptor is a regulator of the α-synuclein gene driving risk of Parkinson’s disease. Science. 2017;357:891–8. PubMed PMC

Hirsova P, Ibrahim SH, Verma VK, et al. Extracellular vesicles in liver pathobiology: small particles with big impact. Hepatology. 2016;64:2219–33. PubMed PMC

Hyenne V, Apaydin A, Rodriguez D, et al. RAL-1 controls multivesicular body biogenesis and exosome secretion. J Cell Biol. 2015;211:27–37. PubMed PMC

Minciacchi VR, Freeman MR, Di Vizio D. Extracellular vesicles in cancer: exosomes, microvesicles and the emerging role of large oncosomes. Semin Cell Dev Biol. 2015;40:41–51. PubMed PMC

Maas SLN, Breakefield XO, Weaver AM. Extracellular vesicles: unique intercellular delivery vehicles. Trends Cell Biol. 2017;27:172–88. PubMed PMC

Povero D, Eguchi A, Li H, et al. Circulating extracellular vesicles with specific proteome and liver microRNAs are potential biomarkers for liver injury in experimental fatty liver disease. PLoS One. 2014;9:e113651. PubMed PMC

Raposo G, Stoorvogel W. Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol. 2013;200:373–83. PubMed PMC

Povero D, Eguchi A, Niesman IR, et al. Lipid-induced toxicity stimulates hepatocytes to release angiogenic microparticles that require Vanin-1 for uptake by endothelial cells. Sci Signal. 2013;6:ra88. PubMed PMC

Deng ZB, Liu Y, Liu C, et al. Immature myeloid cells induced by a high-fat diet contribute to liver inflammation. Hepatology. 2009;50:1412–20. PubMed PMC

Tomita K, Kabashima A, Freeman BL, et al. Mixed lineage kinase 3 mediates the induction of CXCL10 by a STAT1-dependent mechanism during hepatocyte lipotoxicity. J Cell Biochem. 2017;118:3249–59. PubMed PMC

Charlton M, Krishnan A, Viker K, et al. Fast food diet mouse: novel small animal model of NASH with ballooning, progressive fibrosis, and high physiological fidelity to the human condition. Am J Physiol Gastrointest Liver Physiol. 2011;301:G825–G834. PubMed PMC

Mauer AS, Hirsova P, Maiers JL, et al. Inhibition of sphingosine 1-phosphate signaling ameliorates murine nonalcoholic steatohepatitis. Am J Physiol Gastrointest Liver Physiol. 2017;312:G300–G313. PubMed PMC

Povero D, Panera N, Eguchi A, et al. Lipid-induced hepatocyte-derived extracellular vesicles regulate hepatic stellate cell via microRNAs targeting PPAR-γ. Cell Mol Gastroenterol Hepatol. 2015;1:646–63. PubMed PMC

Garcia-Martinez I, Santoro N, Chen Y, et al. Hepatocyte mitochondrial DNA drives nonalcoholic steatohepatitis by activation of TLR9. J Clin Invest. 2016;126:859–64. PubMed PMC

Schaefer L. Complexity of danger: the diverse nature of damage-associated molecular patterns. J Biol Chem. 2014;289:35237–45. PubMed PMC

Kornek M, Lynch M, Mehta SH, et al. Circulating microparticles as disease-specific biomarkers of severity of inflammation in patients with hepatitis C or nonalcoholic steatohepatitis. Gastroenterology. 2012;143:448–58. PubMed PMC

Brett SI, Lucien F, Guo C, et al. Immunoaffinity based methods are superior to kits for purification of prostate derived extracellular vesicles from plasma samples. Prostate. 2017;77:1335–43. PubMed

Liang K, Liu F, Fan J, et al. Nanoplasmonic quantification of tumor-derived extracellular vesicles in plasma microsamples for diagnosis and treatment monitoring. Nat Biomed Eng. 2017;1:0021. PubMed PMC

Tkach M, Kowal J, Zucchetti AE, et al. Qualitative differences in T-cell activation by dendritic cell-derived extracellular vesicle subtypes. Embo J. 2017;36:3012–28. PubMed PMC

Kubes P, Mehal WZ. Sterile inflammation in the liver. Gastroenterology. 2012;143:1158–72. PubMed

Heymann F, Tacke F. Immunology in the liver-from homeostasis to disease. Nat Rev Gastroenterol Hepatol. 2016;13:88–110. PubMed

Koyama Y, Brenner DA. Liver inflammation and fibrosis. J Clin Invest. 2017;127:55–64. PubMed PMC

Buzas EI, György B, Nagy G, et al. Emerging role of extracellular vesicles in inflammatory diseases. Nat Rev Rheumatol. 2014;10:356–64. PubMed

Huang S, Rutkowsky JM, Snodgrass RG, et al. Saturated fatty acids activate TLR-mediated proinflammatory signaling pathways. J Lipid Res. 2012;53:2002–13. PubMed PMC

Li L, Chen L, Hu L, et al. Nuclear factor high-mobility group box1 mediating the activation of Toll-like receptor 4 signaling in hepatocytes in the early stage of nonalcoholic fatty liver disease in mice. Hepatology. 2011;54:1620–30. PubMed

Jia L, Vianna CR, Fukuda M, et al. Hepatocyte Toll-like receptor 4 regulates obesity-induced inflammation and insulin resistance. Nat Commun. 2014;5:3878. PubMed PMC

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;47:571–9. PubMed PMC

Miura K, Kodama Y, Inokuchi S, et al. Toll-like receptor 9 promotes steatohepatitis by induction of interleukin-1beta in mice. Gastroenterology. 2010;139:323–34. PubMed PMC

Kahraman A, Schlattjan M, Kocabayoglu P, et al. Major histocompatibility complex class I-related chains A and B (MIC A/B): a novel role in nonalcoholic steatohepatitis. Hepatology. 2010;51:92–102. PubMed

Sutti S, Jindal A, Bruzzì S, et al. Is there a role for adaptive immunity in nonalcoholic steatohepatitis? World J Hepatol. 2015;7:1725–9. PubMed PMC

Krenkel O, Tacke F. Liver macrophages in tissue homeostasis and disease. Nat Rev Immunol. 2017;17:306–21. PubMed

Dixon LJ, Barnes M, Tang H, et al. Kupffer cells in the liver. Compr Physiol. 2013;3:785–97. PubMed PMC

Scott CL, Zheng F, De Baetselier P, et al. Bone marrow-derived monocytes give rise to self-renewing and fully differentiated Kupffer cells. Nat Commun. 2016;7:10321. PubMed PMC

Itoh M, Suganami T, Kato H, et al. CD11c+ resident macrophages drive hepatocyte death-triggered liver fibrosis in a murine model of nonalcoholic steatohepatitis. JCI Insight. 2017;2 PubMed PMC

Cullen SP, Henry CM, Kearney CJ, et al. Fas/CD95-induced chemokines can serve as "find-me" signals for apoptotic cells. Mol Cell. 2013;49:1034–48. PubMed

Canbay A, Feldstein AE, Higuchi H, et al. Kupffer cell engulfment of apoptotic bodies stimulates death ligand and cytokine expression. Hepatology. 2003;38:1188–98. PubMed

Miura K, Yang L, van Rooijen N, et al. Hepatic recruitment of macrophages promotes nonalcoholic steatohepatitis through CCR2. Am J Physiol Gastrointest Liver Physiol. 2012;302:G1310–G1321. PubMed PMC

Tosello-Trampont AC, Landes SG, Nguyen V, et al. Kuppfer cells trigger nonalcoholic steatohepatitis development in diet-induced mouse model through tumor necrosis factor-α production. J Biol Chem. 2012;287:40161–72. PubMed PMC

Tomita K, Freeman BL, Bronk SF, et al. CXCL10-mediates macrophage, but not other innate immune cells-associated inflammation in murine nonalcoholic steatohepatitis. Sci Rep. 2016;6:28786. PubMed PMC

Zhang X, Shen J, Man K, et al. CXCL10 plays a key role as an inflammatory mediator and a non-invasive biomarker of non-alcoholic steatohepatitis. J Hepatol. 2014;61:1365–75. PubMed

Murray PJ, Allen JE, Biswas SK, et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity. 2014;41:14–20. PubMed PMC

Greuter T, Malhi H, Gores GJ, et al. Therapeutic opportunities for alcoholic steatohepatitis and nonalcoholic steatohepatitis: exploiting similarities and differences in pathogenesis. JCI Insight. 2017;2 PubMed PMC

Rensen SS, Bieghs V, Xanthoulea S, et al. Neutrophil-derived myeloperoxidase aggravates non-alcoholic steatohepatitis in low-density lipoprotein receptor-deficient mice. PLoS One. 2012;7:e52411. PubMed PMC

Talukdar S, Oh DY, Bandyopadhyay G, et al. Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase. Nat Med. 2012;18:1407–12. PubMed PMC

Jorch SK, Kubes P. An emerging role for neutrophil extracellular traps in noninfectious disease. Nat Med. 2017;23:279–87. PubMed

Rotman Y, Sanyal AJ. Current and upcoming pharmacotherapy for non-alcoholic fatty liver disease. Gut. 2017;66:180–90. PubMed

Lanthier N. Targeting Kupffer cells in non-alcoholic fatty liver disease/non-alcoholic steatohepatitis: Why and how? World J Hepatol. 2015;7:2184–8. PubMed PMC

Barreyro FJ, Holod S, Finocchietto PV, et al. The pan-caspase inhibitor emricasan (IDN-6556) decreases liver injury and fibrosis in a murine model of non-alcoholic steatohepatitis. Liver Int. 2015;35:953–66. PubMed

Loomba R, Lawitz E, Mantry PS, et al. The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: a randomized, phase 2 trial. Hepatology. 2017 PubMed PMC

Shiffman M, Freilich B, Vuppalanchi R, et al. LP37: a placebo-controlled, multicenter, double-blind, randomised trial of emricasan in subjects with non-alcoholic fatty liver disease (NAFLD) and raised transaminases. J Hepatol. 2015;62:S282–S82.

Lefebvre E, Hashiguchi T, Jenkins H, et al. Anti-fibrotic and anti-inflammatory activity of the dual CCR2 and CCR5 antagonist cenicriviroc in a mouse model of NASH. Hepatology. 2013;58:221–2.

Friedman SL, Ratziu V, Harrison SA, et al. A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis. Hepatology. 2017 PubMed PMC

Tomita K, Kohli R, MacLaurin BL, et al. Mixed-lineage kinase 3 pharmacological inhibition attenuates murine nonalcoholic steatohepatitis. JCI Insight. 2017;2 PubMed PMC

Mayer L, Sandborn WJ, Stepanov Y, et al. Anti-IP-10 antibody (BMS-936557) for ulcerative colitis: a phase II randomised study. Gut. 2014;63:442–50. PubMed PMC

Moore KJ, Freeman MW. Scavenger receptors in atherosclerosis: beyond lipid uptake. Arterioscler Thromb Vasc Biol. 2006;26:1702–11. PubMed

Traber PG, Zomer E. Therapy of experimental NASH and fibrosis with galectin inhibitors. PLoS One. 2013;8:e83481. PubMed PMC

Harrison SA, Marri SR, Chalasani N, et al. Randomised clinical study: GR-MD-02, a galectin-3 inhibitor, vs. placebo in patients having non-alcoholic steatohepatitis with advanced fibrosis. Aliment Pharmacol Ther. 2016;44(11–12):1183–98. PubMed

Odegaard JI, Ricardo-Gonzalez RR, Red Eagle A, et al. Alternative M2 activation of kupffer cells by PPARdelta ameliorates obesity-induced insulin resistance. Cell Metab. 2008;7:496–507. PubMed PMC

Ratziu V, Harrison SA, Francque S, et al. Elafibranor, an agonist of the peroxisome proliferator-activated receptor-α and -δ, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology. 2016;150:2084–84. PubMed

Miura K, Yang L, van Rooijen N, et al. Toll-like receptor 2 and palmitic acid cooperatively contribute to the development of nonalcoholic steatohepatitis through inflammasome activation in mice. Hepatology. 2013;57:577–89. PubMed PMC

Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet. 2015;385:956–65. PubMed PMC

Rho-associated protein kinase 1 inhibition in hepatocytes attenuates nonalcoholic steatohepatitis

Lipid-induced endothelial vascular cell adhesion molecule 1 promotes nonalcoholic steatohepatitis pathogenesis

Soluble Endoglin as a Potential Biomarker of Nonalcoholic Steatohepatitis (NASH) Development, Participating in Aggravation of NASH-Related Changes in Mouse Liver

Hepatocyte apoptosis is tumor promoting in murine nonalcoholic steatohepatitis