{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T05:04:01Z","timestamp":1791867841908,"version":"4.3.4"},"reference-count":202,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2022,10,6]],"date-time":"2022-10-06T00:00:00Z","timestamp":1665014400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Metabolic (dysfunction) associated fatty liver disease (MAFLD) is one of the most prevalent liver diseases and has no approved therapeutics. The high failure rates witnessed in late-phase MAFLD drug trials reflect the complexity of the disease, and how the disease develops and progresses remains to be fully understood. In vitro, human disease models play a pivotal role in mechanistic studies to unravel novel disease drivers and in drug testing studies to evaluate human-specific responses. This review focuses on MAFLD disease modeling using human cell and organoid models. The spectrum of patient-derived primary cells and immortalized cell lines employed to model various liver parenchymal and non-parenchymal cell types essential for MAFLD development and progression is discussed. Diverse forms of cell culture platforms utilized to recapitulate tissue-level pathophysiology in different stages of the disease are also reviewed.<\/jats:p>","DOI":"10.3390\/ijms231911850","type":"journal-article","created":{"date-parts":[[2022,10,8]],"date-time":"2022-10-08T23:39:31Z","timestamp":1665272371000},"page":"11850","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Advancements in MAFLD Modeling with Human Cell and Organoid Models"],"prefix":"10.3390","volume":"23","author":[{"given":"Shi-Xiang","family":"Wang","sequence":"first","affiliation":[{"name":"Guangzhou Laboratory, No. 9 Xing Dao Huan Bei Road, Guangzhou International Bio Island, Guangzhou 510005, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji-Song","family":"Yan","sequence":"additional","affiliation":[{"name":"Guangzhou Laboratory, No. 9 Xing Dao Huan Bei Road, Guangzhou International Bio Island, Guangzhou 510005, China"},{"name":"School of Life Sciences, Yunnan University, Kunming 650500, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun-Shen","family":"Chan","sequence":"additional","affiliation":[{"name":"Guangzhou Laboratory, No. 9 Xing Dao Huan Bei Road, Guangzhou International Bio Island, Guangzhou 510005, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1038\/nrgastro.2013.41","article-title":"Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis","volume":"10","author":"Anstee","year":"2013","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1053\/j.gastro.2014.07.056","article-title":"Pathological features of fatty liver disease","volume":"147","author":"Yeh","year":"2014","journal-title":"Gastroenterology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1038\/s41581-021-00519-y","article-title":"Association of metabolic dysfunction-associated fatty liver disease with kidney disease","volume":"18","author":"Wang","year":"2022","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1016\/j.jhep.2019.06.021","article-title":"The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: A systematic review and meta-analysis","volume":"71","author":"Younossi","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1146\/annurev-pathol-012615-044224","article-title":"Nonalcoholic Fatty Liver Disease: Pathogenesis and Disease Spectrum","volume":"11","author":"Hardy","year":"2016","journal-title":"Annu. Rev. Pathol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1999","DOI":"10.1053\/j.gastro.2019.11.312","article-title":"MAFLD: A Consensus-Driven Proposed Nomenclature for Metabolic Associated Fatty Liver Disease","volume":"158","author":"Eslam","year":"2020","journal-title":"Gastroenterology"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Le Garf, S., Negre, V., Anty, R., and Gual, P. (2021). Metabolic Fatty Liver Disease in Children: A Growing Public Health Problem. Biomedicines, 9.","DOI":"10.3390\/biomedicines9121915"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1016\/j.jhep.2021.10.025","article-title":"The global NAFLD policy review and preparedness index: Are countries ready to address this silent public health challenge?","volume":"76","author":"Lazarus","year":"2022","journal-title":"J. Hepatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1002\/hep.29466","article-title":"Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease","volume":"67","author":"Estes","year":"2018","journal-title":"Hepatology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1559","DOI":"10.1056\/NEJMoa2029349","article-title":"Prospective Study of Outcomes in Adults with Nonalcoholic Fatty Liver Disease","volume":"385","author":"Sanyal","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1038\/s41574-021-00507-z","article-title":"Emerging therapeutic approaches for the treatment of NAFLD and type 2 diabetes mellitus","volume":"17","author":"Ferguson","year":"2021","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2123","DOI":"10.1136\/gutjnl-2021-326874","article-title":"Current therapies and new developments in NASH","volume":"71","author":"Dufour","year":"2022","journal-title":"Gut"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1016\/j.jhep.2017.09.003","article-title":"Genetics and epigenetics of NAFLD and NASH: Clinical impact","volume":"68","author":"Eslam","year":"2018","journal-title":"J. Hepatol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1784","DOI":"10.1053\/j.gastro.2015.08.011","article-title":"Heritability of Hepatic Fibrosis and Steatosis Based on a Prospective Twin Study","volume":"149","author":"Loomba","year":"2015","journal-title":"Gastroenterology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1038\/s41575-019-0212-0","article-title":"Genetic contributions to NAFLD: Leveraging shared genetics to uncover systems biology","volume":"17","author":"Eslam","year":"2020","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1728","DOI":"10.1053\/j.gastro.2016.01.037","article-title":"Genetic Factors That Affect Risk of Alcoholic and Nonalcoholic Fatty Liver Disease","volume":"150","author":"Anstee","year":"2016","journal-title":"Gastroenterology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.1056\/NEJMoa1712191","article-title":"A Protein-Truncating HSD17B13 Variant and Protection from Chronic Liver Disease","volume":"378","author":"Cheng","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"37085","DOI":"10.1074\/jbc.M111.290114","article-title":"Expression and characterization of a PNPLA3 protein isoform (I148M) associated with nonalcoholic fatty liver disease","volume":"286","author":"Huang","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2998","DOI":"10.1002\/hep.32063","article-title":"Modeling PNPLA3-Associated NAFLD Using Human-Induced Pluripotent Stem Cells","volume":"74","author":"Tilson","year":"2021","journal-title":"Hepatology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1194\/jlr.M011205","article-title":"Pnpla3\/Adiponutrin deficiency in mice does not contribute to fatty liver disease or metabolic syndrome","volume":"52","author":"Basantani","year":"2011","journal-title":"J. Lipid Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1111\/hepr.12587","article-title":"Patatin-like phospholipase domain-containing protein 3 is involved in hepatic fatty acid and triglyceride metabolism through X-box binding protein 1 and modulation of endoplasmic reticulum stress in mice","volume":"46","author":"Ochi","year":"2016","journal-title":"Hepatol. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.0959-9673.2006.00465.x","article-title":"Mouse models in non-alcoholic fatty liver disease and steatohepatitis research","volume":"87","author":"Anstee","year":"2006","journal-title":"Int. J. Exp. Pathol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1016\/j.jhep.2008.02.011","article-title":"Fructose consumption as a risk factor for non-alcoholic fatty liver disease","volume":"48","author":"Ouyang","year":"2008","journal-title":"J. Hepatol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1961","DOI":"10.1002\/hep.23535","article-title":"Increased fructose consumption is associated with fibrosis severity in patients with nonalcoholic fatty liver disease","volume":"51","author":"Abdelmalek","year":"2010","journal-title":"Hepatology"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Jegatheesan, P., and De Bandt, J.P. (2017). Fructose and NAFLD: The Multifaceted Aspects of Fructose Metabolism. Nutrients, 9.","DOI":"10.3390\/nu9030230"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1016\/S0016-5085(98)70599-2","article-title":"Steatohepatitis: A tale of two \u201chits\u201d?","volume":"114","author":"Day","year":"1998","journal-title":"Gastroenterology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1002\/hep.31518","article-title":"Multiple Parallel Hits Hypothesis in Nonalcoholic Fatty Liver Disease: Revisited After a Decade","volume":"73","author":"Tilg","year":"2021","journal-title":"Hepatology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1016\/j.cmet.2017.04.001","article-title":"Gut Microbiome-Based Metagenomic Signature for Non-invasive Detection of Advanced Fibrosis in Human Nonalcoholic Fatty Liver Disease","volume":"25","author":"Loomba","year":"2017","journal-title":"Cell Metab."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1038\/s41591-018-0061-3","article-title":"Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women","volume":"24","author":"Hoyles","year":"2018","journal-title":"Nat. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1406","DOI":"10.1038\/s41467-019-09455-9","article-title":"A gut microbiome signature for cirrhosis due to nonalcoholic fatty liver disease","volume":"10","author":"Caussy","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"R1147","DOI":"10.1016\/j.cub.2017.09.019","article-title":"The liver","volume":"27","author":"Trefts","year":"2017","journal-title":"Curr. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1016\/j.jhep.2010.11.021","article-title":"Presence and significance of microvesicular steatosis in nonalcoholic fatty liver disease","volume":"55","author":"Tandra","year":"2011","journal-title":"J. Hepatol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1097\/MOG.0000000000000716","article-title":"Statins for treatment of chronic liver disease","volume":"37","author":"Marrache","year":"2021","journal-title":"Curr. Opin. Gastroenterol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/S0002-9343(99)00271-5","article-title":"Association of nonalcoholic fatty liver disease with insulin resistance","volume":"107","author":"Marchesini","year":"1999","journal-title":"Am. J. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1038\/nature13478","article-title":"The role of hepatic lipids in hepatic insulin resistance and type 2 diabetes","volume":"510","author":"Perry","year":"2014","journal-title":"Nature"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4361","DOI":"10.1172\/JCI86013","article-title":"Insulin receptor Thr1160 phosphorylation mediates lipid-induced hepatic insulin resistance","volume":"126","author":"Petersen","year":"2016","journal-title":"J. Clin. Investig."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1444","DOI":"10.1053\/j.gastro.2012.03.003","article-title":"Intrahepatic diacylglycerol content is associated with hepatic insulin resistance in obese subjects","volume":"142","author":"Magkos","year":"2012","journal-title":"Gastroenterology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1172\/JCI30400","article-title":"Inhibition of protein kinase Cepsilon prevents hepatic insulin resistance in nonalcoholic fatty liver disease","volume":"117","author":"Samuel","year":"2007","journal-title":"J. Clin. Investig."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1016\/j.cell.2005.02.001","article-title":"Mitochondria, oxidants, and aging","volume":"120","author":"Balaban","year":"2005","journal-title":"Cell"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1016\/j.molcel.2011.08.038","article-title":"ROS-mediated p53 induction of Lpin1 regulates fatty acid oxidation in response to nutritional stress","volume":"44","author":"Assaily","year":"2011","journal-title":"Mol. Cell"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"25187","DOI":"10.1038\/srep25187","article-title":"Characterization of primary human hepatocyte spheroids as a model system for drug-induced liver injury, liver function and disease","volume":"6","author":"Bell","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"20170362","DOI":"10.1098\/rstb.2017.0362","article-title":"Modelling non-alcoholic fatty liver disease in human hepatocyte-like cells","volume":"373","author":"Lyall","year":"2018","journal-title":"Philos. Trans. R. Soc. B Biol. Sci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/S1386-6346(01)00172-3","article-title":"Enhanced GLUT2 gene expression in an oleic acid-induced in vitro fatty liver model","volume":"23","author":"Okamoto","year":"2002","journal-title":"Hepatol. Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.cbi.2006.11.004","article-title":"A human hepatocellular in vitro model to investigate steatosis","volume":"165","author":"Donato","year":"2007","journal-title":"Chem. Biol. Interact."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1038\/cr.2009.73","article-title":"Lipid accumulation in hepatocytes induces fibrogenic activation of hepatic stellate cells","volume":"19","author":"Wobser","year":"2009","journal-title":"Cell Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1825","DOI":"10.1002\/hep.31857","article-title":"Functional Characterization of Organoids Derived From Irreversibly Damaged Liver of Patients With NASH","volume":"74","author":"McCarron","year":"2021","journal-title":"Hepatology"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1471","DOI":"10.1053\/j.gastro.2020.06.010","article-title":"Human Pluripotent Stem Cell-Derived Organoids as Models of Liver Disease","volume":"159","author":"Ramli","year":"2020","journal-title":"Gastroenterology"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1089\/scd.2015.0383","article-title":"Modeling Nonalcoholic Fatty Liver Disease with Human Pluripotent Stem Cell-Derived Immature Hepatocyte-Like Cells Reveals Activation of PLIN2 and Confirms Regulatory Functions of Peroxisome Proliferator-Activated Receptor Alpha","volume":"25","author":"Graffmann","year":"2016","journal-title":"Stem Cells Dev."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2591","DOI":"10.1053\/j.gastro.2021.02.050","article-title":"Induced Pluripotent Stem Cell-derived Hepatocytes From Patients With Nonalcoholic Fatty Liver Disease Display a Disease-specific Gene Expression Profile","volume":"160","author":"Duwaerts","year":"2021","journal-title":"Gastroenterology"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1016\/j.cmet.2019.05.007","article-title":"Modeling Steatohepatitis in Humans with Pluripotent Stem Cell-Derived Organoids","volume":"30","author":"Ouchi","year":"2019","journal-title":"Cell Metab."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"5734","DOI":"10.1021\/acsbiomaterials.0c00682","article-title":"Modeling Human Nonalcoholic Fatty Liver Disease (NAFLD) with an Organoids-on-a-Chip System","volume":"6","author":"Wang","year":"2020","journal-title":"ACS Biomater. Sci. Eng."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1002\/hep.31108","article-title":"Cenicriviroc Treatment for Adults With Nonalcoholic Steatohepatitis and Fibrosis: Final Analysis of the Phase 2b CENTAUR Study","volume":"72","author":"Ratziu","year":"2020","journal-title":"Hepatology"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1016\/j.cgh.2014.04.014","article-title":"Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: A systematic review and meta-analysis of paired-biopsy studies","volume":"13","author":"Singh","year":"2015","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1393","DOI":"10.1002\/hep.26937","article-title":"The portal inflammatory infiltrate and ductular reaction in human nonalcoholic fatty liver disease","volume":"59","author":"Gadd","year":"2014","journal-title":"Hepatology"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1998","DOI":"10.1002\/hep.23599","article-title":"Accumulation of natural killer T cells in progressive nonalcoholic fatty liver disease","volume":"51","author":"Syn","year":"2010","journal-title":"Hepatology"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1130","DOI":"10.1038\/labinvest.2015.95","article-title":"Pivotal role of liver sinusoidal endothelial cells in NAFLD\/NASH progression","volume":"95","author":"Miyao","year":"2015","journal-title":"Lab. Investig."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1913","DOI":"10.1053\/j.gastro.2019.11.311","article-title":"Mechanisms of Fibrosis Development in Nonalcoholic Steatohepatitis","volume":"158","author":"Schwabe","year":"2020","journal-title":"Gastroenterology"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1500","DOI":"10.1002\/hep.24611","article-title":"Pathogen- or damage-associated molecular patterns during nonalcoholic fatty liver disease development","volume":"54","author":"Alisi","year":"2011","journal-title":"Hepatology"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1172\/JCI24282","article-title":"Liver fibrosis","volume":"115","author":"Bataller","year":"2005","journal-title":"J. Clin. Investig."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1038\/nri3623","article-title":"Liver fibrosis and repair: Immune regulation of wound healing in a solid organ","volume":"14","author":"Pellicoro","year":"2014","journal-title":"Nat. Rev. Immunol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2537","DOI":"10.1016\/j.cell.2021.04.015","article-title":"Mechanisms and disease consequences of nonalcoholic fatty liver disease","volume":"184","author":"Loomba","year":"2021","journal-title":"Cell"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1557","DOI":"10.1002\/hep.29085","article-title":"Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: Systematic review and meta-analysis","volume":"65","author":"Dulai","year":"2017","journal-title":"Hepatology"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1016\/S0016-5085(99)70506-8","article-title":"Nonalcoholic fatty liver disease: A spectrum of clinical and pathological severity","volume":"116","author":"Matteoni","year":"1999","journal-title":"Gastroenterology"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1016\/j.jhep.2008.01.026","article-title":"Ballooned hepatocytes in steatohepatitis: The value of keratin immunohistochemistry for diagnosis","volume":"48","author":"Lackner","year":"2008","journal-title":"J. Hepatol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1002\/hep.27068","article-title":"High-fat diet triggers Mallory-Denk body formation through misfolding and crosslinking of excess keratin 8","volume":"60","author":"Kucukoglu","year":"2014","journal-title":"Hepatology"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.jnutbio.2013.10.010","article-title":"Role of immunodeficient animal models in the development of fructose induced NAFLD","volume":"25","author":"Bhattacharjee","year":"2014","journal-title":"J. Nutr. Biochem."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2300","DOI":"10.3748\/wjg.v18.i19.2300","article-title":"Animal models of nonalcoholic fatty liver disease\/nonalcoholic steatohepatitis","volume":"18","author":"Takahashi","year":"2012","journal-title":"World J. Gastroenterol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1053\/j.gastro.2016.05.051","article-title":"Comparison of Gene Expression Patterns Between Mouse Models of Nonalcoholic Fatty Liver Disease and Liver Tissues From Patients","volume":"151","author":"Teufel","year":"2016","journal-title":"Gastroenterology"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1111\/j.1440-1746.2008.05733.x","article-title":"Differential effect of oleic and palmitic acid on lipid accumulation and apoptosis in cultured hepatocytes","volume":"24","author":"Ricchi","year":"2009","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.33594\/000000288","article-title":"Palmitate and Fructose Interact to Induce Human Hepatocytes to Produce Pro-Fibrotic Transcriptional Responses in Hepatic Stellate Cells Exposed to Conditioned Media","volume":"54","author":"Piras","year":"2020","journal-title":"Cell Physiol. Biochem."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1034","DOI":"10.1038\/s42255-020-0261-2","article-title":"Fructose stimulated de novo lipogenesis is promoted by inflammation","volume":"2","author":"Todoric","year":"2020","journal-title":"Nat. Metab."},{"key":"ref_72","first-page":"95","article-title":"Quantification and mechanisms of oleic acid-induced steatosis in HepG2 cells","volume":"2","author":"Cui","year":"2010","journal-title":"Am. J. Transl. Res."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1002\/hep.21752","article-title":"Palmitic acid induces production of proinflammatory cytokine interleukin-8 from hepatocytes","volume":"46","author":"Barve","year":"2007","journal-title":"Hepatology"},{"key":"ref_74","first-page":"183","article-title":"In vitro treatment of HepG2 cells with saturated fatty acids reproduces mitochondrial dysfunction found in nonalcoholic steatohepatitis","volume":"8","year":"2015","journal-title":"Dis. Model. Mech."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"2226","DOI":"10.1038\/s41598-022-06143-5","article-title":"Exendin-4 alleviates steatosis in an in vitro cell model by lowering FABP1 and FOXA1 expression via the Wnt\/-catenin signaling pathway","volume":"12","author":"Khalifa","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"e13532","DOI":"10.14814\/phy2.13532","article-title":"In vitro cellular models of human hepatic fatty acid metabolism: Differences between Huh7 and HepG2 cell lines in human and fetal bovine culturing serum","volume":"5","author":"Gunn","year":"2017","journal-title":"Physiol. Rep."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.nutres.2018.02.004","article-title":"Arctigenin protects against steatosis in WRL68 hepatocytes through activation of phosphoinositide 3-kinase\/protein kinase B and AMP-activated protein kinase pathways","volume":"52","author":"Chen","year":"2018","journal-title":"Nutr. Res."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.taap.2016.04.007","article-title":"Advantageous use of HepaRG cells for the screening and mechanistic study of drug-induced steatosis","volume":"302","author":"Tolosa","year":"2016","journal-title":"Toxicol. Appl. Pharm."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"120904","DOI":"10.1016\/j.biomaterials.2021.120904","article-title":"A scalable and sensitive steatosis chip with long-term perfusion of in situ differentiated HepaRG organoids","volume":"275","author":"Teng","year":"2021","journal-title":"Biomaterials"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1038\/labinvest.3700590","article-title":"Microarray analyses and molecular profiling of steatosis induction in immortalized human hepatocytes","volume":"87","author":"Vinciguerra","year":"2007","journal-title":"Lab. Investig."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Mahli, A., Seitz, T., Beckroge, T., Freese, K., Thasler, W.E., Benkert, M., Dietrich, P., Weiskirchen, R., Bosserhoff, A., and Hellerbrand, C. (2019). Bone Morphogenetic Protein-8B Expression is Induced in Steatotic Hepatocytes and Promotes Hepatic Steatosis and Inflammation In Vitro. Cells, 8.","DOI":"10.3390\/cells8050457"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"11585","DOI":"10.1038\/s41598-019-47737-w","article-title":"The TM6SF2 E167K genetic variant induces lipid biosynthesis and reduces apolipoprotein B secretion in human hepatic 3D spheroids","volume":"9","author":"Prill","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Parafati, M., Bae, S.H., Kirby, R.J., Fitzek, M., Iyer, P., Engkvist, O., Smith, D.M., and Malany, S. (2020). Pluripotent Stem Cell-Derived Hepatocytes Phenotypic Screening Reveals Small Molecules Targeting the CDK2\/4-C\/EBPalpha\/DGAT2 Pathway Preventing ER-Stress Induced Lipid Accumulation. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21249557"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"101931","DOI":"10.1016\/j.isci.2020.101931","article-title":"A human pluripotent stem cell model for the analysis of metabolic dysfunction in hepatic steatosis","volume":"24","author":"Sinton","year":"2021","journal-title":"iScience"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1038\/282615a0","article-title":"Controlled synthesis of HBsAg in a differentiated human liver carcinoma-derived cell line","volume":"282","author":"Aden","year":"1979","journal-title":"Nature"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/j.tox.2004.02.009","article-title":"Use of a human-derived liver cell line for the detection of cytoprotective, antigenotoxic and cogenotoxic agents","volume":"198","author":"Wu","year":"2004","journal-title":"Toxicology"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"16","DOI":"10.3390\/jfb6010016","article-title":"Poly(vinyl alcohol)\/gelatin Hydrogels Cultured with HepG2 Cells as a 3D Model of Hepatocellular Carcinoma: A Morphological Study","volume":"6","author":"Moscato","year":"2015","journal-title":"J. Funct. Biomater."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1002\/hep.1840380426","article-title":"Defective hepatic mitochondrial respiratory chain in patients with nonalcoholic steatohepatitis","volume":"38","author":"Rubio","year":"2003","journal-title":"Hepatology"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1053\/jhep.2003.50316","article-title":"Cytokines and NASH: A pilot study of the effects of lifestyle modification and vitamin E","volume":"38","author":"Kugelmas","year":"2003","journal-title":"Hepatology"},{"key":"ref_90","first-page":"1549","article-title":"Levels of serum hyaluronic acid, TNF-alpha and IL-8 in patients with nonalcoholic steatohepatitis","volume":"52","author":"Bahcecioglu","year":"2005","journal-title":"Hepatogastroenterology"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.mce.2015.09.027","article-title":"C1q\/TNF-Related Protein 9 (CTRP9) attenuates hepatic steatosis via the autophagy-mediated inhibition of endoplasmic reticulum stress","volume":"417","author":"Jung","year":"2015","journal-title":"Mol. Cell Endocrinol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"R522","DOI":"10.1152\/ajpregu.00110.2013","article-title":"CTRP9 transgenic mice are protected from diet-induced obesity and metabolic dysfunction","volume":"305","author":"Peterson","year":"2013","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1804","DOI":"10.4161\/cc.24940","article-title":"Cellular immortalization and neoplastic transformation: Simultaneous, sequential or independent? Telomeres, telomerase or karyotypic variations?","volume":"12","author":"Mondello","year":"2013","journal-title":"Cell Cycle"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.cotox.2020.08.003","article-title":"Primary hepatocyte cultures for liver disease modeling","volume":"25","author":"Vinken","year":"2021","journal-title":"Curr. Opin. Toxicol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1053\/j.gastro.2008.04.038","article-title":"Hepatocyte-specific Smad7 expression attenuates TGF-beta-mediated fibrogenesis and protects against liver damage","volume":"135","author":"Dooley","year":"2008","journal-title":"Gastroenterology"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1016\/j.bbrc.2020.03.128","article-title":"Humanin attenuates palmitate-induced hepatic lipid accumulation and insulin resistance via AMPK-mediated suppression of the mTOR pathway","volume":"526","author":"Kwon","year":"2020","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"6077","DOI":"10.1002\/jcp.26449","article-title":"WISP1 promotes non-alcoholic fatty liver disease and skeletal muscle insulin resistance via TLR4\/JNK signaling","volume":"233","author":"Jung","year":"2018","journal-title":"J. Cell Physiol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"3981","DOI":"10.1074\/jbc.RA117.000885","article-title":"Maresin 1 attenuates NAFLD by suppression of endoplasmic reticulum stress via AMPK-SERCA2b pathway","volume":"293","author":"Jung","year":"2018","journal-title":"J. Biol. Chem."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"730","DOI":"10.21037\/atm-2020-ubih-05","article-title":"Mechanism of idiosyncratic drug induced liver injury (DILI): Unresolved basic issues","volume":"9","author":"Teschke","year":"2021","journal-title":"Ann. Transl. Med."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/j.cell.2014.11.050","article-title":"Long-term culture of genome-stable bipotent stem cells from adult human liver","volume":"160","author":"Huch","year":"2015","journal-title":"Cell"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1724","DOI":"10.1038\/nprot.2016.097","article-title":"Culture and establishment of self-renewing human and mouse adult liver and pancreas 3D organoids and their genetic manipulation","volume":"11","author":"Broutier","year":"2016","journal-title":"Nat. Protoc."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1591","DOI":"10.1016\/j.cell.2018.11.013","article-title":"Long-Term Expansion of Functional Mouse and Human Hepatocytes as 3D Organoids","volume":"175","author":"Hu","year":"2018","journal-title":"Cell"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1016\/j.stem.2018.10.018","article-title":"In Vitro Expansion of Primary Human Hepatocytes with Efficient Liver Repopulation Capacity","volume":"23","author":"Zhang","year":"2018","journal-title":"Cell Stem Cell"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1038\/s41422-018-0103-x","article-title":"Expansion and differentiation of human hepatocyte-derived liver progenitor-like cells and their use for the study of hepatotropic pathogens","volume":"29","author":"Fu","year":"2019","journal-title":"Cell Res."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1002\/hep.29483","article-title":"Self-assembled liver organoids recapitulate hepatobiliary organogenesis in vitro","volume":"67","author":"Vyas","year":"2018","journal-title":"Hepatology"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1038\/s41556-019-0359-5","article-title":"Modelling liver cancer initiation with organoids derived from directly reprogrammed human hepatocytes","volume":"21","author":"Sun","year":"2019","journal-title":"Nat. Cell Biol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1016\/j.stem.2019.04.017","article-title":"Probing the Tumor Suppressor Function of BAP1 in CRISPR-Engineered Human Liver Organoids","volume":"24","author":"Artegiani","year":"2019","journal-title":"Cell Stem Cell"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.1136\/gutjnl-2020-321611","article-title":"Risk of severe illness from COVID-19 in patients with metabolic dysfunction-associated fatty liver disease and increased fibrosis scores","volume":"69","author":"Targher","year":"2020","journal-title":"Gut"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1016\/j.jhep.2020.03.044","article-title":"Non-alcoholic fatty liver diseases in patients with COVID-19: A retrospective study","volume":"73","author":"Ji","year":"2020","journal-title":"J. Hepatol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1200","DOI":"10.1038\/s41401-022-00874-x","article-title":"Histological assessment based on liver biopsy: The value and challenges in NASH drug development","volume":"43","author":"Tong","year":"2022","journal-title":"Acta Pharm. Sin."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1126\/science.282.5391.1145","article-title":"Embryonic stem cell lines derived from human blastocysts","volume":"282","author":"Thomson","year":"1998","journal-title":"Science"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1016\/j.cell.2007.11.019","article-title":"Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors","volume":"131","author":"Takahashi","year":"2007","journal-title":"Cell"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"972","DOI":"10.1136\/gut.2005.064477","article-title":"Identification of expandable human hepatic progenitors which differentiate into mature hepatic cells in vivo","volume":"54","author":"Nowak","year":"2005","journal-title":"Gut"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1002\/hep.21582","article-title":"Directed differentiation of human embryonic stem cells into functional hepatic cells","volume":"45","author":"Cai","year":"2007","journal-title":"Hepatology"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1002\/hep.23354","article-title":"Highly efficient generation of human hepatocyte-like cells from induced pluripotent stem cells","volume":"51","author":"Noto","year":"2010","journal-title":"Hepatology"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1038\/nature10116","article-title":"Induction of functional hepatocyte-like cells from mouse fibroblasts by defined factors","volume":"475","author":"Huang","year":"2011","journal-title":"Nature"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1038\/nature10263","article-title":"Direct conversion of mouse fibroblasts to hepatocyte-like cells by defined factors","volume":"475","author":"Sekiya","year":"2011","journal-title":"Nature"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1038\/nature13020","article-title":"Mouse liver repopulation with hepatocytes generated from human fibroblasts","volume":"508","author":"Zhu","year":"2014","journal-title":"Nature"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"2190","DOI":"10.1016\/j.celrep.2018.01.087","article-title":"A Roadmap for Human Liver Differentiation from Pluripotent Stem Cells","volume":"22","author":"Ang","year":"2018","journal-title":"Cell Rep."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"409","DOI":"10.5966\/sctm.2012-0160","article-title":"Highly efficient differentiation of functional hepatocytes from human induced pluripotent stem cells","volume":"2","author":"Ma","year":"2013","journal-title":"Stem Cells Transl. Med."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1016\/j.jhep.2018.12.028","article-title":"Generation of hepatobiliary organoids from human induced pluripotent stem cells","volume":"70","author":"Wu","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"102763","DOI":"10.1016\/j.scr.2022.102763","article-title":"In vitro differentiation of pluripotent stem cells into hepatocyte like cells-Basic principles and current progress","volume":"61","author":"Graffmann","year":"2022","journal-title":"Stem Cell Res."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1634\/stemcells.2007-0718","article-title":"Efficient differentiation of hepatocytes from human embryonic stem cells exhibiting markers recapitulating liver development in vivo","volume":"26","author":"Hay","year":"2008","journal-title":"Stem Cells"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"3120","DOI":"10.1172\/JCI43267","article-title":"Induced pluripotent stem cell-derived hepatocytes have the functional and proliferative capabilities needed for liver regeneration in mice","volume":"120","author":"Espejel","year":"2010","journal-title":"J. Clin. Investig."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1002\/hep.23506","article-title":"Generation of functional hepatocytes from human embryonic stem cells under chemically defined conditions that recapitulate liver development","volume":"51","author":"Touboul","year":"2010","journal-title":"Hepatology"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1016\/j.jhep.2019.06.030","article-title":"Generation of expandable human pluripotent stem cell-derived hepatocyte-like liver organoids","volume":"71","author":"Mun","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1038\/nature12271","article-title":"Vascularized and functional human liver from an iPSC-derived organ bud transplant","volume":"499","author":"Takebe","year":"2013","journal-title":"Nature"},{"key":"ref_128","doi-asserted-by":"crossref","unstructured":"Shi, Y., Inoue, H., Takahashi, J., and Yamanaka, S. (2020). Induced pluripotent stem cell technology: Venturing into the second decade. Principles of Tissue Engineering, Academic Press.","DOI":"10.1016\/B978-0-12-818422-6.00095-2"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1038\/s41586-022-04593-5","article-title":"Chemical reprogramming of human somatic cells to pluripotent stem cells","volume":"605","author":"Guan","year":"2022","journal-title":"Nature"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/j.phrs.2019.04.016","article-title":"Elafibranor restricts lipogenic and inflammatory responses in a human skin stem cell-derived model of NASH","volume":"144","author":"Boeckmans","year":"2019","journal-title":"Pharmacol. Res."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1038\/s41575-018-0082-x","article-title":"The role of macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis","volume":"16","author":"Kazankov","year":"2019","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"580968","DOI":"10.3389\/fimmu.2020.580968","article-title":"CD4(+) T Cells Mediate the Development of Liver Fibrosis in High Fat Diet-Induced NAFLD in Humanized Mice","volume":"11","author":"Her","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"97","DOI":"10.4049\/jimmunol.1501175","article-title":"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","volume":"196","author":"Rau","year":"2016","journal-title":"J. Immunol."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"536","DOI":"10.15252\/embj.201591857","article-title":"p38\u03b3 and p38\u03b4 reprogram liver metabolism by modulating neutrophil infiltration","volume":"35","author":"Matesanz","year":"2016","journal-title":"EMBO J."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1038\/s41591-019-0379-5","article-title":"Platelet GPIb\u03b1 is a mediator and potential interventional target for NASH and subsequent liver cancer","volume":"25","author":"Malehmir","year":"2019","journal-title":"Nat. Med."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"1278","DOI":"10.1016\/j.jhep.2019.02.012","article-title":"Role of liver sinusoidal endothelial cells in non-alcoholic fatty liver disease","volume":"70","author":"Hammoutene","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1136\/gut.2004.042127","article-title":"Human hepatic stellate cell lines, LX-1 and LX-2: New tools for analysis of hepatic fibrosis","volume":"54","author":"Xu","year":"2005","journal-title":"Gut"},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1016\/j.jnutbio.2008.06.003","article-title":"Extracts of Lindera obtusiloba induce antifibrotic effects in hepatic stellate cells via suppression of a TGF-beta-mediated profibrotic gene expression pattern","volume":"20","author":"Ruehl","year":"2009","journal-title":"J. Nutr. Biochem."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.jhep.2010.02.027","article-title":"New insights into the antifibrotic effects of sorafenib on hepatic stellate cells and liver fibrosis","volume":"53","author":"Wang","year":"2010","journal-title":"J. Hepatol."},{"key":"ref_140","first-page":"919","article-title":"Sodium valproate blocks the transforming growth factor (TGF)-beta1 autocrine loop and attenuates the TGF-beta1-induced collagen synthesis in a human hepatic stellate cell line","volume":"28","author":"Watanabe","year":"2011","journal-title":"Int. J. Mol. Med."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.cyto.2014.07.251","article-title":"Development of a cytokine-producing immortalized murine Kupffer cell line","volume":"70","author":"Wang","year":"2014","journal-title":"Cytokine"},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1038\/nbt.3294","article-title":"Directed differentiation of cholangiocytes from human pluripotent stem cells","volume":"33","author":"Ogawa","year":"2015","journal-title":"Nat. Biotechnol."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1038\/nbt.3275","article-title":"Cholangiocytes derived from human induced pluripotent stem cells for disease modeling and drug validation","volume":"33","author":"Sampaziotis","year":"2015","journal-title":"Nat. Biotechnol."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"3948","DOI":"10.1039\/C7AN00865A","article-title":"Changes induced by non-alcoholic fatty liver disease in liver sinusoidal endothelial cells and hepatocytes: Spectroscopic imaging of single live cells at the subcellular level","volume":"142","author":"Kochan","year":"2017","journal-title":"Analyst"},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.stem.2018.05.027","article-title":"Generation of Hepatic Stellate Cells from Human Pluripotent Stem Cells Enables In Vitro Modeling of Liver Fibrosis","volume":"23","author":"Coll","year":"2018","journal-title":"Cell Stem Cell"},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1016\/j.stem.2020.06.007","article-title":"Generation of Functional Liver Sinusoidal Endothelial Cells from Human Pluripotent Stem-Cell-Derived Venous Angioblasts","volume":"27","author":"Gage","year":"2020","journal-title":"Cell Stem Cell"},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"750044","DOI":"10.3389\/fmed.2021.750044","article-title":"Gene Signatures Detect Damaged Liver Sinusoidal Endothelial Cells in Chronic Liver Diseases","volume":"8","author":"Verhulst","year":"2021","journal-title":"Front. Med."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1038\/s41419-020-03356-2","article-title":"PU.1 drives specification of pluripotent stem cell-derived endothelial cells to LSEC-like cells","volume":"12","author":"Talon","year":"2021","journal-title":"Cell Death Dis."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1038\/s41598-020-80689-0","article-title":"LECT2 as a hepatokine links liver steatosis to inflammation via activating tissue macrophages in NASH","volume":"11","author":"Takata","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"1629","DOI":"10.1016\/j.stemcr.2021.04.010","article-title":"An integrated analysis of human myeloid cells identifies gaps in in vitro models of in vivo biology","volume":"16","author":"Rajab","year":"2021","journal-title":"Stem Cell Rep."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1186\/s13619-021-00089-1","article-title":"Emerging liver organoid platforms and technologies","volume":"10","author":"Lam","year":"2021","journal-title":"Cell Regen."},{"key":"ref_152","unstructured":"Burt, A.D., Ferrell, L.D., and H\u00fcbscher, S.G. (2017). MacSween\u2019s Pathology of the Liver-Elsevier, Elsevier. [7th ed.]."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"1885","DOI":"10.1038\/s41591-019-0660-7","article-title":"Three-dimensional spatially resolved geometrical and functional models of human liver tissue reveal new aspects of NAFLD progression","volume":"25","author":"Kucken","year":"2019","journal-title":"Nat. Med."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"22765","DOI":"10.1038\/s41598-021-01951-7","article-title":"A 3D primary human cell-based in vitro model of non-alcoholic steatohepatitis for efficacy testing of clinical drug candidates","volume":"11","author":"Strobel","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_155","doi-asserted-by":"crossref","unstructured":"Sendi, H., Mead, I., Wan, M., Mehrab-Mohseni, M., Koch, K., Atala, A., Bonkovsky, H.L., and Bishop, C.E. (2018). miR-122 inhibition in a human liver organoid model leads to liver inflammation, necrosis, steatofibrosis and dysregulated insulin signaling. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0200847"},{"key":"ref_156","doi-asserted-by":"crossref","unstructured":"Pingitore, P., Sasidharan, K., Ekstrand, M., Prill, S., Linden, D., and Romeo, S. (2019). Human Multilineage 3D Spheroids as a Model of Liver Steatosis and Fibrosis. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20071629"},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"359","DOI":"10.14218\/JCTH.2020.00015","article-title":"A 3D Human Liver Model of Nonalcoholic Steatohepatitis","volume":"8","author":"Duriez","year":"2020","journal-title":"J. Clin. Transl. Hepatol."},{"key":"ref_158","doi-asserted-by":"crossref","unstructured":"Gori, M., Simonelli, M.C., Giannitelli, S.M., Businaro, L., Trombetta, M., and Rainer, A. (2016). Investigating Nonalcoholic Fatty Liver Disease in a Liver-on-a-Chip Microfluidic Device. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0159729"},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"204","DOI":"10.3748\/wjg.v23.i2.204","article-title":"Three-dimensional perfused human in vitro model of non-alcoholic fatty liver disease","volume":"23","author":"Kostrzewski","year":"2017","journal-title":"World J. Gastroenterol."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/j.actbio.2021.07.013","article-title":"Modeling nonalcoholic fatty liver disease on a liver lobule chip with dual blood supply","volume":"134","author":"Du","year":"2021","journal-title":"Acta Biomater."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"e2007425","DOI":"10.1002\/smll.202007425","article-title":"Bioengineered Multicellular Liver Microtissues for Modeling Advanced Hepatic Fibrosis Driven Through Non-Alcoholic Fatty Liver Disease","volume":"17","author":"Cho","year":"2021","journal-title":"Small"},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1039\/C7IB00027H","article-title":"Microengineered cultures containing human hepatic stellate cells and hepatocytes for drug development","volume":"9","author":"Davidson","year":"2017","journal-title":"Integr. Biol."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"e90954","DOI":"10.1172\/jci.insight.90954","article-title":"Development of an in vitro human liver system for interrogating nonalcoholic steatohepatitis","volume":"1","author":"Feaver","year":"2016","journal-title":"JCI Insight"},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.1016\/j.jhep.2016.01.016","article-title":"Gene expression profiling in human precision cut liver slices in response to the FXR agonist obeticholic acid","volume":"64","author":"Ijssennagger","year":"2016","journal-title":"J. Hepatol."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/j.cmet.2019.06.017","article-title":"Generation of Human Fatty Livers Using Custom-Engineered Induced Pluripotent Stem Cells with Modifiable SIRT1 Metabolism","volume":"30","author":"Takeishi","year":"2019","journal-title":"Cell Metab."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1038\/s41578-021-00279-y","article-title":"Engineering organoids","volume":"6","author":"Hofer","year":"2021","journal-title":"Nat. Rev. Mater."},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1016\/j.jcmgh.2017.11.012","article-title":"Bioengineered Liver Models for Drug Testing and Cell Differentiation Studies","volume":"5","author":"Underhill","year":"2018","journal-title":"Cell Mol. Gastroenterol. Hepatol."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1055\/s-0041-1731016","article-title":"Bioengineered Liver Models for Investigating Disease Pathogenesis and Regenerative Medicine","volume":"41","author":"Kukla","year":"2021","journal-title":"Semin. Liver Dis."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"e2110054","DOI":"10.1002\/adma.202110054","article-title":"Volumetric Bioprinting of Organoids and Optically Tuned Hydrogels to Build Liver-Like Metabolic Biofactories","volume":"34","author":"Bernal","year":"2022","journal-title":"Adv. Mater."},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1038\/nbt.2989","article-title":"Microfluidic organs-on-chips","volume":"32","author":"Bhatia","year":"2014","journal-title":"Nat. Biotechnol."},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1038\/s41578-018-0034-7","article-title":"Advances in organ-on-a-chip engineering","volume":"3","author":"Zhang","year":"2018","journal-title":"Nat. Rev. Mater."},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"1898","DOI":"10.1021\/acsbiomaterials.6b00699","article-title":"In Vitro Intestinal and Liver Models for Toxicity Testing","volume":"3","author":"Orbach","year":"2017","journal-title":"ACS Biomater. Sci. Eng."},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"109393","DOI":"10.1016\/j.celrep.2021.109393","article-title":"Modeling alcohol-associated liver disease in a human Liver-Chip","volume":"36","author":"Nawroth","year":"2021","journal-title":"Cell Rep."},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1002\/hep4.1647","article-title":"Human Nonalcoholic Steatohepatitis on a Chip","volume":"5","author":"Freag","year":"2021","journal-title":"Hepatol. Commun."},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1038\/nbt1361","article-title":"Microscale culture of human liver cells for drug development","volume":"26","author":"Khetani","year":"2008","journal-title":"Nat. Biotechnol."},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1007\/s12072-018-9913-7","article-title":"Precision-cut liver slices: A versatile tool to advance liver research","volume":"13","author":"Palma","year":"2019","journal-title":"Hepatol. Int."},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"1382","DOI":"10.1136\/gutjnl-2020-321299","article-title":"Guidelines on the use of liver biopsy in clinical practice from the British Society of Gastroenterology, the Royal College of Radiologists and the Royal College of Pathology","volume":"69","author":"Neuberger","year":"2020","journal-title":"Gut"},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1002\/jbm.b.33384","article-title":"Three dimensional culture of HepG2 liver cells on a rat decellularized liver matrix for pharmacological studies","volume":"104","author":"Hussein","year":"2016","journal-title":"J. Biomed. Mater. Res. B Appl. Biomater."},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"13079","DOI":"10.1038\/srep13079","article-title":"Decellularized human liver as a natural 3D-scaffold for liver bioengineering and transplantation","volume":"5","author":"Mazza","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1038\/s41577-021-00639-3","article-title":"Immune cell-mediated features of non-alcoholic steatohepatitis","volume":"22","author":"Huby","year":"2022","journal-title":"Nat. Rev. Immunol."},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"1026","DOI":"10.1002\/hep.30506","article-title":"The Role of Innate Immune Cells in Nonalcoholic Steatohepatitis","volume":"70","author":"Cai","year":"2019","journal-title":"Hepatology"},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1038\/s42255-019-0044-9","article-title":"Liver macrophages regulate systemic metabolism through non-inflammatory factors","volume":"1","author":"Morgantini","year":"2019","journal-title":"Nat. Metab."},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"4383","DOI":"10.1038\/s41467-018-06318-7","article-title":"Single cell RNA sequencing of human liver reveals distinct intrahepatic macrophage populations","volume":"9","author":"MacParland","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1038\/s41586-019-1631-3","article-title":"Resolving the fibrotic niche of human liver cirrhosis at single-cell level","volume":"575","author":"Ramachandran","year":"2019","journal-title":"Nature"},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1038\/s41575-019-0210-2","article-title":"Adaptive immunity: An emerging player in the progression of NAFLD","volume":"17","author":"Sutti","year":"2020","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/j.freeradbiomed.2018.06.015","article-title":"B2-Lymphocyte responses to oxidative stress-derived antigens contribute to the evolution of nonalcoholic fatty liver disease (NAFLD)","volume":"124","author":"Sutti","year":"2018","journal-title":"Free Radic. Biol. Med."},{"key":"ref_187","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1002\/hep4.1041","article-title":"Hepatic Natural Killer T-cell and CD8+ T-cell Signatures in Mice with Nonalcoholic Steatohepatitis","volume":"1","author":"Bhattacharjee","year":"2017","journal-title":"Hepatol. Commun."},{"key":"ref_188","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/j.tips.2018.01.003","article-title":"Specialized Proresolving Mediators: Enhancing Nonalcoholic Steatohepatitis and Fibrosis Resolution","volume":"39","author":"Musso","year":"2018","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_189","doi-asserted-by":"crossref","first-page":"24194","DOI":"10.1038\/s41598-021-03679-w","article-title":"Dual role of neutrophils in modulating liver injury and fibrosis during development and resolution of diet-induced murine steatohepatitis","volume":"11","author":"Kim","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_190","doi-asserted-by":"crossref","first-page":"100148","DOI":"10.1016\/j.jhepr.2020.100148","article-title":"Stratification of patients in NASH clinical trials: A pitfall for trial success","volume":"2","author":"Ampuero","year":"2020","journal-title":"JHEP Rep."},{"key":"ref_191","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1038\/nrgastro.2010.191","article-title":"Animal models of nonalcoholic fatty liver disease","volume":"8","author":"Hebbard","year":"2011","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_192","doi-asserted-by":"crossref","first-page":"1884","DOI":"10.1002\/hep.31897","article-title":"A Systematic Review of Animal Models of NAFLD Finds High-Fat, High-Fructose Diets Most Closely Resemble Human NAFLD","volume":"74","author":"Im","year":"2021","journal-title":"Hepatology"},{"key":"ref_193","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1055\/s-0035-1562942","article-title":"Diagnosis and Assessment of NAFLD: Definitions and Histopathological Classification","volume":"35","author":"Burt","year":"2015","journal-title":"Semin. Liver Dis."},{"key":"ref_194","doi-asserted-by":"crossref","first-page":"2467","DOI":"10.1111\/j.1572-0241.1999.01377.x","article-title":"Nonalcoholic steatohepatitis: A proposal for grading and staging the histological lesions","volume":"94","author":"Brunt","year":"1999","journal-title":"Am. J. Gastroenterol."},{"key":"ref_195","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1002\/hep.20701","article-title":"Design and validation of a histological scoring system for nonalcoholic fatty liver disease","volume":"41","author":"Kleiner","year":"2005","journal-title":"Hepatology"},{"key":"ref_196","unstructured":"U.S. Food & Drug Administration (2022, August 01). Noncirrhotic Nonalcoholic Steatohepatitis with Liver Fibrosis: Developing Drugs for Treatment Guidance for Industry (Draft Guidance), Available online: https:\/\/www.fda.gov\/regulatory-information\/search-fda-guidance-documents\/noncirrhotic-nonalcoholic-steatohepatitis-liver-fibrosis-developing-drugs-treatment."},{"key":"ref_197","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1007\/BF00784350","article-title":"Fatty macroregenerative nodule in non-steatotic liver cirrhosis. A morphologic study","volume":"415","author":"Terada","year":"1989","journal-title":"Virchows Arch. A Pathol. Anat. Histopathol."},{"key":"ref_198","doi-asserted-by":"crossref","first-page":"2180","DOI":"10.1002\/hep.26072","article-title":"Hepatic fat loss in advanced nonalcoholic steatohepatitis: Are alterations in serum adiponectin the cause?","volume":"57","author":"Samer","year":"2013","journal-title":"Hepatology"},{"key":"ref_199","doi-asserted-by":"crossref","unstructured":"Kessoku, T., Kobayashi, T., Tanaka, K., Yamamoto, A., Takahashi, K., Iwaki, M., Ozaki, A., Kasai, Y., Nogami, A., and Honda, Y. (2021). The Role of Leaky Gut in Nonalcoholic Fatty Liver Disease: A Novel Therapeutic Target. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22158161"},{"key":"ref_200","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1038\/nrgastro.2009.33","article-title":"Endocrine and liver interaction: The role of endocrine pathways in NASH","volume":"6","author":"Loria","year":"2009","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_201","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1007\/s13238-017-0436-0","article-title":"New insight into inter-organ crosstalk contributing to the pathogenesis of non-alcoholic fatty liver disease (NAFLD)","volume":"9","author":"Zhang","year":"2018","journal-title":"Protein Cell"},{"key":"ref_202","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1016\/j.jhep.2020.01.013","article-title":"NAFLD as a driver of chronic kidney disease","volume":"72","author":"Byrne","year":"2020","journal-title":"J. Hepatol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/19\/11850\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:47:11Z","timestamp":1760143631000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/19\/11850"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,6]]},"references-count":202,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2022,10]]}},"alternative-id":["ijms231911850"],"URL":"https:\/\/doi.org\/10.3390\/ijms231911850","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,6]]}}}