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Cited by 49Liver Disease Diagnosis and TreatmentDiet, Metabolism, and DiseaseLiver physiology and pathology

A human liver chimeric mouse model for non-alcoholic fatty liver disease

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Bissig-Choisat, Beatrice, Alves-Bezerra, Michele, Zorman, Barry, Ochsner, Scott A., Barzi, Mercedes, Legras, Xavier, Yang, Diane, Borowiak, Malgorzata +10 more·2021·JHEP Reports
DOI 10.1016/j.jhepr.2021.100281PMC PMC8138774
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Abstract

BACKGROUND & AIMS: The accumulation of neutral lipids within hepatocytes underlies non-alcoholic fatty liver disease (NAFLD), which affects a quarter of the world's population and is associated with hepatitis, cirrhosis, and hepatocellular carcinoma. Despite insights gained from both human and animal studies, our understanding of NAFLD pathogenesis remains limited. To better study the molecular changes driving the condition we aimed to generate a humanised NAFLD mouse model. METHODS: ) mice, populated their livers with human hepatocytes, and fed them a Western-type diet for 12 weeks. RESULTS: Within the same chimeric liver, human hepatocytes developed pronounced steatosis whereas murine hepatocytes remained normal. Unbiased metabolomics and lipidomics revealed signatures of clinical NAFLD. Transcriptomic analyses showed that molecular responses diverged sharply between murine and human hepatocytes, demonstrating stark species differences in liver function. Regulatory network analysis indicated close agreement between our model and clinical NAFLD with respect to transcriptional control of cholesterol biosynthesis. CONCLUSIONS: These NAFLD xenograft mice reveal an unexpected degree of evolutionary divergence in food metabolism and offer a physiologically relevant, experimentally tractable model for studying the pathogenic changes invoked by steatosis. LAY SUMMARY: Fatty liver disease is an emerging health problem, and as there are no good experimental animal models, our understanding of the condition is poor. We here describe a novel humanised mouse system and compare it with clinical data. The results reveal that the human cells in the mouse liver develop fatty liver disease upon a Western-style fatty diet, whereas the mouse cells appear normal. The molecular signature (expression profiles) of the human cells are distinct from the mouse cells and metabolic analysis of the humanised livers mimic the ones observed in humans with fatty liver. This novel humanised mouse system can be used to study human fatty liver disease.

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  • Humanized mice have already shown promise in modelling chronic liver diseases like MASLD and human liver viral infections.

    “Such humanized mice have already shown promise in modelling of chronic liver diseases like MASLD(56) and human liver viral infections(57).”

    From The liver as a central "hub" of the immune system: pathophysiological implications (2025) · cites this paper as [56]

  • Mice exposed to ethanol exhibit an imbalance between the naive and memory compartments of their CD4+ T cells due to increased homeostatic proliferation of memory cells.

    “while mice exposed to ethanol exhibit an imbalance between the naive and memory compartments of their CD4+ T cells due to increased homeostatic proliferation of memory cells (56, 57).”

    From The liver as a central "hub" of the immune system: pathophysiological implications (2025) · cites this paper as [56]

    The Methods and Results describe humanised mice fed a Western diet or normal chow, not mice exposed to ethanol. The Discussion notes that the mice are immunodeficient, but our copy does not address naive or memory CD4+ T-cell compartments or homeostatic proliferation (searched: ethanol, CD4 T cells, memory-cell proliferation). (LLM, conf=0.77)

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References 50 · Cited by 49

Research works printed but not linked: 44

  1. [1]Younossi Z.M. Koenig A.B. Abdelatif D. Fazel Y. Henry L. Wymer M. Global epidemiology of nonalcoholic fatty liver disease – meta-analytic assessment of prevalence, incidence, and outcomes Hepatology 64 2016 73 84 26707365
  2. [2]Alves-Bezerra M. Cohen D.E. Triglyceride metabolism in the liver Compr Physiol 8 2017 1 8 29357123 PMC6376873
  3. [3]Bessone F. Razori M.V. Roma M.G. Molecular pathways of nonalcoholic fatty liver disease development and progression Cell Mol Life Sci 76 2019 99 128 30343320 PMC11105781
  4. [4]Font-Burgada J. Sun B. Karin M. Obesity and cancer: the oil that feeds the flame Cell Metab 23 2016 48 62 26771116
  5. [5]Hebbard L. George J. Animal models of nonalcoholic fatty liver disease Nat Rev Gastroenterol Hepatol 8 2011 35 44 21119613
  6. [6]Han J. Dzierlenga A.L. Lu Z. Billheimer D.D. Torabzadeh E. Lake A.D. Metabolomic profiling distinction of human nonalcoholic fatty liver disease progression from a common rat model Obesity (Silver Spring) 25 2017 1069 1076 28452429 PMC5513172
  7. [7]Barzi M. Pankowicz F.P. Zorman B. Liu X. Legras X. Yang D. A novel humanized mouse lacking murine P450 oxidoreductase for studying human drug metabolism Nat Commun 8 2017 39 28659616 PMC5489481
  8. [8]Bissig-Choisat B. Wang L. Legras X. Saha P.K. Chen L. Bell P. Development and rescue of human familial hypercholesterolaemia in a xenograft mouse model Nat Commun 6 2015 7339 26081744 PMC4557302
  9. [9]Bissig K.D. Wieland S.F. Tran P. Isogawa M. Le T.T. Chisari F.V. Human liver chimeric mice provide a model for hepatitis B and C virus infection and treatment J Clin Invest 120 2010 924 930 20179355 PMC2827952
  10. [11]Ochsner S.A. Abraham D. Martin K. Ding W. McOwiti A. Kankanamge W. The Signaling Pathways Project, an integrated 'omics knowledgebase for mammalian cellular signaling pathways Sci Data 6 2019 252 31672983 PMC6823428
  11. [12]Mi H. Huang X. Muruganujan A. Tang H. Mills C. Kang D. PANTHER version 11: expanded annotation data from Gene Ontology and Reactome pathways, and data analysis tool enhancements Nucleic Acids Res 45 2017 D183 D189 27899595 PMC5210595
  12. [13]Fabregat A. Sidiropoulos K. Garapati P. Gillespie M. Hausmann K. Haw R. The reactome pathway knowledgebase Nucleic Acids Res 44 2016 D481 D487 26656494 PMC4702931
  13. [14]Ochsner S.A. Pillich R.T. McKenna N.J. Consensus transcriptional regulatory networks of coronavirus-infected human cells Sci Data 7 2020 314 32963239 PMC7509801
  14. [15]Bissig K.D. Le T.T. Woods N.B. Verma I.M. Repopulation of adult and neonatal mice with human hepatocytes: a chimeric animal model Proc Natl Acad Sci USA 104 2007 20507 20511 18077355 PMC2154461
  15. [16]Azuma H. Paulk N. Ranade A. Dorrell C. Al-Dhalimy M. Ellis E. Robust expansion of human hepatocytes in Fah-/-/Rag2-/-/Il2rg-/- mice Nat Biotechnol 25 2007 903 910 17664939 PMC3404624
  16. [17]Olson E.N. Arnold H.H. Rigby P.W. Wold B.J. Know your neighbors: three phenotypes in null mutants of the myogenic bHLH gene MRF4 Cell 85 1996 1 4 8620528
  17. [18]Valera A. Perales J.C. Hatzoglou M. Bosch F. Expression of the neomycin-resistance (neo) gene induces alterations in gene expression and metabolism Hum Gene Ther 5 1994 449 456 7914094
  18. [19]Arguello G. Balboa E. Arrese M. Zanlungo S. Recent insights on the role of cholesterol in non-alcoholic fatty liver disease Biochim Biophys Acta 1852 2015 1765 1778 26027904
  19. [20]Zhong G. Kirkwood J. Won K.J. Tjota N. Jeong H. Isoherranen N. Characterization of vitamin A metabolome in human livers with and without nonalcoholic fatty liver disease J Pharmacol Exp Ther 370 2019 92 103 31043436 PMC6548984
  20. [21]Puri P. Baillie R.A. Wiest M.M. Mirshahi F. Choudhury J. Cheung O. A lipidomic analysis of nonalcoholic fatty liver disease Hepatology 46 2007 1081 1090 17654743
  21. [22]Gorden D.L. Ivanova P.T. Myers D.S. McIntyre J.O. VanSaun M.N. Wright J.K. Increased diacylglycerols characterize hepatic lipid changes in progression of human nonalcoholic fatty liver disease; comparison to a murine model PloS One 6 2011 e22775 PMC3153459 21857953
  22. [23]Wattacheril J. Seeley E.H. Angel P. Chen H. Bowen B.P. Lanciault C. Differential intrahepatic phospholipid zonation in simple steatosis and nonalcoholic steatohepatitis PloS One 8 2013 e57165 PMC3581520 23451176
  23. [24]Luukkonen P.K. Zhou Y. Sadevirta S. Leivonen M. Arola J. Oresic M. Hepatic ceramides dissociate steatosis and insulin resistance in patients with non-alcoholic fatty liver disease J Hepatol 64 2016 1167 1175 26780287
  24. [25]Chiappini F. Coilly A. Kadar H. Gual P. Tran A. Desterke C. Metabolism dysregulation induces a specific lipid signature of nonalcoholic steatohepatitis in patients Sci Rep 7 2017 46658 28436449 PMC5402394
  25. [26]Arendt B.M. Comelli E.M. Ma D.W. Lou W. Teterina A. Kim T. Altered hepatic gene expression in nonalcoholic fatty liver disease is associated with lower hepatic n-3 and n-6 polyunsaturated fatty acids Hepatology 61 2015 1565 1578 25581263
  26. [27]Videla L.A. Rodrigo R. Araya J. Poniachik J. Oxidative stress and depletion of hepatic long-chain polyunsaturated fatty acids may contribute to nonalcoholic fatty liver disease Free Radic Biol Med 37 2004 1499 1507 15454290
  27. [28]Min H.K. Kapoor A. Fuchs M. Mirshahi F. Zhou H. Maher J. Increased hepatic synthesis and dysregulation of cholesterol metabolism is associated with the severity of nonalcoholic fatty liver disease Cell Metab 15 2012 665 674 22560219 PMC3361911
  28. [29]Govaere O. Cockell S. Tiniakos D. Queen R. Younes R. Vacca M. Transcriptomic profiling across the nonalcoholic fatty liver disease spectrum reveals gene signatures for steatohepatitis and fibrosis Sci Transl Med 12 2020 eaba4448 33268509
  29. [30]Namjou B. Lingren T. Huang Y. Parameswaran S. Cobb B.L. Stanaway I.B. GWAS and enrichment analyses of non-alcoholic fatty liver disease identify new trait-associated genes and pathways across eMERGE Network BMC Med 17 2019 135 31311600 PMC6636057
  30. [31]Horton J.D. Goldstein J.L. Brown M.S. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver J Clin Invest 109 2002 1125 1131 11994399 PMC150968
  31. [32]Moslehi A. Hamidi-Zad Z. Role of SREBPs in liver diseases: a mini-review J Clin Transl Hepatol 6 2018 332 338 30271747 PMC6160306
  32. [34]Mao Z. Feng M. Li Z. Zhou M. Xu L. Pan K. ETV5 regulates hepatic fatty acid metabolism through PPAR signaling pathway Diabetes 70 2021 214 226 33093014
  33. [35]Futema M. Plagnol V. Li K. Whittall R.A. Neil H.A. Seed M. Whole exome sequencing of familial hypercholesterolaemia patients negative for LDLR/APOB/PCSK9 mutations J Med Genet 51 2014 537 544 24987033 PMC4112429
  34. [36]Araya J. Rodrigo R. Videla L.A. Thielemann L. Orellana M. Pettinelli P. Increase in long-chain polyunsaturated fatty acid n - 6/n - 3 ratio in relation to hepatic steatosis in patients with non-alcoholic fatty liver disease Clin Sci (Lond) 106 2004 635 643 14720121
  35. [37]Elizondo A. Araya J. Rodrigo R. Poniachik J. Csendes A. Maluenda F. Polyunsaturated fatty acid pattern in liver and erythrocyte phospholipids from obese patients Obesity (Silver Spring) 15 2007 24 31 17228028
  36. [38]Araya J. Rodrigo R. Pettinelli P. Araya A.V. Poniachik J. Videla L.A. Decreased liver fatty acid delta-6 and delta-5 desaturase activity in obese patients Obesity (Silver Spring) 18 2010 1460 1463 19875987
  37. [39]Pettinelli P. Del Pozo T. Araya J. Rodrigo R. Araya A.V. Smok G. Enhancement in liver SREBP-1c/PPAR-alpha ratio and steatosis in obese patients: correlations with insulin resistance and n-3 long-chain polyunsaturated fatty acid depletion Biochim Biophys Acta 1792 2009 1080 1086 19733654
  38. [40]Liu D. Wong C.C. Fu L. Chen H. Zhao L. Li C. Squalene epoxidase drives NAFLD-induced hepatocellular carcinoma and is a pharmaceutical target Sci Transl Med 10 2018 eaap9840 29669855
  39. [41]Dutkowski P. Linecker M. DeOliveira M.L. Mullhaupt B. Clavien P.A. Challenges to liver transplantation and strategies to improve outcomes Gastroenterology 148 2015 307 323 25224524
  40. [42]McCormack L. Petrowsky H. Jochum W. Furrer K. Clavien P.A. Hepatic steatosis is a risk factor for postoperative complications after major hepatectomy: a matched case-control study Ann Surg 245 2007 923 930 17522518 PMC1876953
  41. [43]Romeo S. Kozlitina J. Xing C. Pertsemlidis A. Cox D. Pennacchio L.A. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease Nat Genet 40 2008 1461 1465 18820647 PMC2597056
  42. [44]Geisler C.E. Hepler C. Higgins M.R. Renquist B.J. Hepatic adaptations to maintain metabolic homeostasis in response to fasting and refeeding in mice Nutr Metab 13 2016 62 PMC5037643 27708682
  43. [45]Andrikopoulos S. Massa C.M. Aston-Mourney K. Funkat A. Fam B.C. Hull R.L. Differential effect of inbred mouse strain (C57BL/6, DBA/2, 129T2) on insulin secretory function in response to a high fat diet J Endocrinol 187 2005 45 53 16214940
  44. [46]Wang A.Y. Dhaliwal J. Mouzaki M. Lean non-alcoholic fatty liver disease Clin Nutr 38 2019 975 981 30466956

Authors
Bissig-Choisat, B., Alves-Bezerra, M., Zorman, B., Ochsner, S. A., Barzi, M., Legras, X., Yang, D., Borowiak, M., Dean, A. M., York, R. B., Galvan, N. T. N., Goss, J., Lagor, W. R., Moore, D. D., Cohen, D. E., McKenna, N. J., Sumazin, P., & Bissig, K.-D.
Affiliations
  • Duke University (US)
  • Baylor College of Medicine (US)
  • Texas Children's Hospital (US)
  • Weill Cornell Medicine (US)
Corresponding author
Bissig, Karl-Dimiter
ORCID
Venue
JHEP Reports
Publisher
Elsevier BV
Published
2021-06
Volume
3
Issue
3
Pages
100281
ISSN
2589-5559 (ISSN-L)
DOI
10.1016/j.jhepr.2021.100281
PMC
PMC8138774
OpenAlex
W3138629243
Cited by
49
References
50
Citations by year
2026: 5 · 2025: 9 · 2024: 10 · 2023: 14 · 2022: 7 · 2021: 4
FWCI
6.30
Type
journal article
Language
en
Open access
Licence
Locations
  • JHEP Reports (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • eScholarship (California Digital Library) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
Funders
  • National Cancer Institute
  • National Heart Lung and Blood Institute
  • American Heart Association Inc
  • National Institute of Diabetes and Digestive and Kidney Diseases
Topics
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Keywords
non-alcoholic fatty liver disease, humanized mice, steatosis, Western diet, cholesterol biosynthesis, lipidomics, metabolomics, transcriptomics, regulatory network analysis, hepatocyte metabolism

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