Experimental models of hepatocellular failure based on the isolated and combined effects of etiological factors
Keywords:
liver, combined liver injuries, experimental models, metabolically associated fatty liver disease, alcohol-related liver disease, drug-induced liver disease, in vivo, in vitro
Abstract
Liver diseases remain one of the leading causes of mortality worldwide. The presence of multiple etiological factors in patients poses a particular challenge, often resulting in the development of combined liver injuries. This highlights the growing need for experimental models that simulate such combined hepatic damage. These models allow for the reproduction of metabolic, toxic, and infectious effects in conditions that closely resemble clinical reality. Currently, both in vitro and in vivo models are used for this purpose, each offering specific advantages and limitations. This article provides an overview of existing experimental models of combined liver injury, as well as isolated forms, which serve as a basis for studying pathogenesis and developing effective therapeutic strategies.
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References
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2. Devarbhavi H., Asrani S.K., Arab J.P., et al. Global burden of liver disease: 2023 update. J Hepatol. 2023;79(2):516-537. doi: 10.1016/j.jhep.2023.03.017.
3. Cheemerla S., Balakrishnan M. Global Epidemiology of Chronic Liver Disease. Clin Liver Dis (Hoboken). 2021;4;17(5):365-370. doi: 10.1002/cld.1061.
4. Sandler YU.G., Vinnickaya E.V., Gendrikson L.N., Hajmenova T.YU. i dr. Autoimmunnyj gepatit: kak izbezhat' oshibki? Doktor.Ru. 2017;2(131):15–21. (In Russian)
5. Altamirano J., Miquel R., Katoonizadeh A., et al. A histologic scoring system for prognosis of patients with alcoholic hepatitis. Gastroenterology 2014;146(5):1231–1239. doi: 10.1053/j.gastro.2014.01.018.
6. Thompson W.L., Takebe T. Human liver model systems in a dish. Dev Growth Differ. 2021;63(1):47-58. doi: 10.1111/dgd.12708.
7. Krylov D.P., Rodimova S.A., Karabut M.M., Kuznetsova D.S. Experimental models for studying structural and functional state of the pathological liver (review). Sovremennye tehnologii v medicine 2023;15(4):65. doi: 10.17691/stm2023.15.4.06. (In Russian)
8. Akhtar A. The flaws and human harms of animal experimentation. Camb Q Healthc Ethics 2015;24(4):407–419. doi: 10.1017/s0963180115000079.
9. Mazerkina I.A. Ocenka lekarstvennoj gepatotoksichnosti in vitro na kletochnyh modelyah (obzor). Bezopasnost' i risk farmakoterapii. 2023;11(2):131-144. doi: 10.30895/2312-7821-2023-11-2-351. (In Russian)
10. Aoudjehane L., Gautheron J., Goff W.L., et al. Novel Defatting Strategies Reduce Lipid Accumulation in Primary Human Culture Models of Liver Steatosis. Dis. Model. Mech. 2020;13 doi: 10.1242/dmm.042663.
11. Gómez-Lechón M.J., Donato M.T., Castell J.V., Jover R. Human Hepatocytes as a Tool for Studying Toxicity and Drug Metabolism. Curr. Drug Metab. 2003;4:292–312. doi: 10.2174/1389200033489424.
12. Wilkening S., Stahl F., Bader A. Comparison of Primary Human Hepatocytes and Hepatoma Cell Line Hepg2 with Regard to Their Biotransformation Properties. Drug Metab. Dispos. 2003;31:1035–1042. doi: 10.1124/dmd.31.8.1035.
13. Zeilinger K., Freyer N., Damm G., et al. Cell Sources for in Vitro Human Liver Cell Culture Models. Exp. Biol. Med. 2016;241:1684–1698. doi: 10.1177/1535370216657448.
14. Segovia-Zafra A., Di Zeo-Sánchez D.E., López-Gómez C., et al. Preclinical models of idiosyncratic drug-induced liver injury (iDILI): moving towards prediction. Acta Pharm Sin B. 2021;11(12):3685–726. doi: 10.1016/j.apsb.2021.11.013.
15. Sison-Young R.L., Mitsa D., Jenkins R.E., at al. Comparative Proteomic Characterization of 4 Human Liver-Derived Single Cell Culture Models Reveals Significant Variation in the Capacity for Drug Disposition, Bioactivation, and Detoxication. Toxicological Sciences. 2015;147(2):412-24. doi: 10.1093/toxsci/kfv136.
16. Hu C., Li L. In Vitro Culture of Isolated Primary Hepatocytes and Stem Cell-Derived Hepatocyte-like Cells for Liver Regeneration. Protein Cell. 2015;6:562–574. doi: 10.1007/s13238-015-0180-2
17. Imagawa K., Takayama K., Isoyama S., et al. Generation of a bile salt export pump deficiency model using patient-specific induced pluripotent stem cell-derived hepatocyte-like cells. Sci Rep. 2017;7:41806. doi: 10.1038/srep41806.
18. Polli J.E. In vitro studies are sometimes better than conventional human pharmacokinetic in vivo studies in assessing bioequivalence of immediate-release solid oral dosage forms. AAPS J 2008;10(2): 289–299. doi: 10.1208/s12248-008-9027-6.
19. Gamboa J.M., Leong K.W. In vitro and in vivo models for the study of oral delivery of nanoparticles. Adv Drug Deliv Rev. 2013;15;65(6):800-10. doi: 10.1016/j.addr.2013.01.003.
20. Mackowiak B., Fu Y., Maccioni L., Gao B. Alcohol-associated liver disease. J Clin Invest. 2024;1;134(3):176345. doi: 10.1172/JCI176345.
21. Rastovic U., Bozzano S.F., Riva A., at al. Human Precision-Cut Liver Slices: A Potential Platform to Study Alcohol-Related Liver Disease. Int J Mol Sci. 2023;21;25(1):150. doi: 10.3390/ijms25010150.
22. Bertola A., Mathews S., Ki S.H., at al. Mouse model of chronic and binge ethanol feeding (the NIAAA model). Nat Protoc 2013;8(3):627–637. doi: 10.1038/nprot.2013.032.
23. 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(5):1737–1753. doi: 10.1002/hep.29645.
24. Tsukamoto H., French S.W., Rektelberger R.D., Largman C. Cyclical pattern of blood alcohol levels during continuous intragastric ethanol infusion in rats. Alcohol Clin Exp Res 1985;9(1): 31–37. doi: 10.1111/j.1530-0277.1985.tb05046.
25. Nawroth J.C., Petropolis D.B., Manatakis D.V., et al. Modeling Alcohol-Associated Liver Disease in a Human Liver-Chip. Cell Rep. 2021;36(3):109393. doi: 10.1016/j.celrep.2021.109393.
26. Dewyse L., Reynaert H., van Grunsven L.A. Best Practices and Progress in Precision-Cut Liver Slice Cultures. Int J Mol Sci. 2021;22(13):7137. doi: 10.3390/ijms22137137.
27. de Graaf I.A., Olinga P., de Jager M.H., et al. Preparation and incubation of precision-cut liver and intestinal slices for application in drug metabolism and toxicity studies. Nat Protoc. 2010;5(9):1540-51. doi: 10.1038/nprot.2010.111.
28. Thandra K.C., Barsouk A., Saginala K., et al. Epidemiology of non-alcoholic fatty liver disease and risk of hepatocellular carcinoma progression. Clin Exp Hepatol. 2020;6(4):289-294. doi: 10.5114/ceh.2020.102153.
29. Basaranoglu M., Neuschwander-Tetri B.A. Nonalcoholic Fatty Liver Disease: Clinical Features and Pathogenesis. Gastroenterol Hepatol (N Y). 2006;2(4):282-291.
30. Hansen B.C., Liang Z., Sun F., et al. Nonalcoholic fatty liver disease (NAFLD) in obese rhesus monkeys provides the first animal model that accurately reflects the human condition. FASEB J 2017;31(S1):895.6–895.6. doi: 10.1096/fasebj.31.1_supplement.895.6.
31. Cao L., Xu E., Zheng R., et al. Traditional Chinese medicine Lingguizhugan decoction ameliorate HFD-induced hepatic-lipid deposition in mice by inhibiting STING-mediated inflammation in macrophages. Chin Med. 2022;17(1):7. doi: 10.1186/s13020-021-00559-3.
32. Fang T., Wang H., Pan X., et al. Mouse models of nonalcoholic fatty liver disease (NAFLD): pathomechanisms and pharmacotherapies. Int J Biol Sci. 2022;18(15):5681-5697. doi: 10.7150/ijbs.65044.
33. Ishimoto T., Lanaspa M.A., Rivard C.J., et al. High-fat and high-sucrose (western) diet induces steatohepatitis that is dependent on fructokinase. Hepatology. 2013;58(5):1632-43. doi: 10.1002/hep.26594.
34. Lefere S., Puengel T., Hundertmark J., et al. Differential effects of selective- and pan-PPAR agonists on experimental steatohepatitis and hepatic macrophages. J Hepatol. 2020;73(4):757-770. doi: 10.1016/j.jhep.2020.04.025.
35. Du Y., Broering R., Li X., et al. In Vivo Mouse Models for Hepatitis B Virus Infection and Their Application. Front Immunol. 2021;12:766534. doi: 10.3389/fimmu.2021.766534.
36. Dong R., Zhang B., Zhang X. Liver organoids: an in vitro 3D model for liver cancer study. Cell Biosci. 2022;12(1):152. doi: 10.1186/s13578-022-00890-8.
37. Xu R., Hu P., Li Y., et al. Advances in HBV infection and replication systems in vitro. Virol J. 2021;18(1):105. doi: 10.1186/s12985-021-01580-6.
38. De Crignis E., Hossain T., Romal S., et al. Application of human liver organoids as a patient-derived primary model for HBV infection and related hepatocellular carcinoma. Elife. 2021;10:e60747. doi: 10.7554/eLife.60747.
39. Feng F., Zhao Y. Hepatocellular Carcinoma: Prevention, Diagnosis, and Treatment. Med Princ Pract. 2024;33(5):414-423. doi: 10.1159/000539349.
40. Sundi P.R.I.O., Thipe V.C., Omar M.A., et al. Preclinical human and murine models of hepatocellular carcinoma (HCC). Clin Res Hepatol Gastroenterol. 2024;48(7):102418. doi: 10.1016/j.clinre.2024.102418.
41. Li G., Liu D., Cooper T.K., et al. Successful chemoimmunotherapy against hepatocellular cancer in a novel murine model. J Hepatol. 2017;66(1):75-85. doi: 10.1016/j.jhep.2016.07.044.
42. Blidisel A., Marcovici I., Coricovac D., et al. Experimental Models of Hepatocellular Carcinoma-A Preclinical Perspective. Cancers (Basel). 2021;13(15):3651. doi: 10.3390/cancers13153651.
43. Asrani S.K., Devarbhavi H., Eaton J., Kamath P.S. Burden of liver diseases in the world. J Hepatol. 2019;70:151–171. doi: 10.1016/j.jhep.2018.09.014.
44. Kalligeros M., Vassilopoulos A., Vassilopoulos S., et al. Prevalence of Steatotic Liver Disease (MASLD, MetALD, and ALD) in the United States: NHANES 2017-2020. Clin Gastroenterol Hepatol. 2024;22(6):1330-1332.e4. doi: 10.1016/j.cgh.2023.11.003.
45. Buyco D.G., Martin J., Jeon S., et al. Experimental models of metabolic and alcoholic fatty liver disease. World J Gastroenterol. 2021;27(1):1-18. doi: 10.3748/wjg.v27.i1.1.
46. Genchi V.A., Cignarelli A., Sansone A., et al. Understanding the Role of Alcohol in Metabolic Dysfunction and Male Infertility. Metabolites. 2024;14(11):626. doi: 10.3390/metabo14110626.
47. Hwang S., Ren T., Gao B. Obesity and binge alcohol intake are deadly combination to induce steatohepatitis: A model of high-fat diet and binge ethanol intake. Clin Mol Hepatol. 2020;26(4):586-594. doi: 10.3350/cmh.2020.0100.
48. Cao P., Chao X., Ni H.M., Ding W.X. An Update on Animal Models of Alcohol-Associated Liver Disease. Am J Pathol. 2025;S0002-9440(25):00032-X. doi: 10.1016/j.ajpath.2024.11.011.
49. Schonfeld M., O'Neil M., Villar M.T., et al. A Western diet with alcohol in drinking water recapitulates features of alcohol-associated liver disease in mice. Alcohol Clin Exp Res. 2021;45(10):1980-1993. doi: 10.1111/acer.14700.
50. Benedé-Ubieto R., Estévez-Vázquez O., Guo F., et al. An Experimental DUAL Model of Advanced Liver Damage. Hepatol Commun. 2021;5(6):1051-1068. doi: 10.1002/hep4.1698.
51. Correnti J., Lin C., Brettschneider J., et al. Liver-specific ceramide reduction alleviates steatosis and insulin resistance in alcohol-fed mice. Journal of Lipid Research. 2020;61(7):983-994. doi: 10.1194/jlr.ra119000446.
52. Wang Y., Seitz H.K., Wang X.D.. Moderate alcohol consumption aggravates high-fat diet induced steatohepatitis in rats. Alcohol Clin Exp Res. 2010;34:567–573. doi: 10.1111/j.1530-0277.2009.01122.x.
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Published
27-10-2025
How to Cite
Fominykh Y. A., Nadzhafova K. N. ., Zhdanova I. A., Molchanova M. S., Sonin D. L., Galagudza M. M. Experimental models of hepatocellular failure based on the isolated and combined effects of etiological factors // Patologicheskaya Fiziologiya i Eksperimental’naya Terapiya (Pathological physiology and experimental therapy). 2025. VOL. 69. № 4. PP. 157–167.
Issue
Section
Reviews
