Mouse model of NASH that replicates key features of the human disease and progresses to fibrosis stage 3
Open accessAbstract
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the United States and the world; with no Food and Drug Administration–approved pharmacological treatment available, it remains an area of unmet medical need. In nonalcoholic steatohepatitis (NASH), the most important predictor of clinical outcome is the fibrosis stage. Moreover, the Food and Drug Administration recommends that clinical trials for drugs to treat this disease include patients with fibrosis stage 2 or greater. Therefore, when using animal models for investigating the pathophysiology of NAFLD and for the preclinical evaluation of new drugs, it is important that the animals develop substantial fibrosis. The aim of this study was to develop a mouse model of NAFLD that replicated the disease in humans, including obesity and progressive liver fibrosis. Agouti yellow mutant mice, which have hyperphagia, were fed a Western diet and water containing high‐fructose corn syrup for 16 weeks. Mice became obese and developed glucose intolerance. Their gut microbiota showed dysbiosis with changes that replicate some of the changes described in humans with NASH. They developed NASH with activity scores of 5–6 and fibrosis, which was stage 1 after 16 weeks, and stage 3 after 12 months. Changes in liver gene expression assessed by gene‐set enrichment analysis showed 90% similarity with changes in human patients with NASH. Conclusion: Ay mice, when fed a Western diet similar to that consumed by humans, develop obesity and NASH with liver histology, including fibrosis, and gene expression changes that are highly similar to the disease in humans.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Another MASH model combines the Agouti yellow mutation driving hyperphagia with a Western diet and fructose water; mice start to develop fibrosis after 16 weeks.
“Similarly, another MASH model combines the Agouti yellow mutation driving hyperphagia with a Western diet and fructose water, where mice start to develop fibrosis after 16 weeks (231).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [231]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Design and validation of a histological scoring system for nonalcoholic fatty liver disease†
Kleiner, D. E., Brunt, E. M., Van Natta, M., Behling, C., Contos, M. J., Cummings, O. W., Ferrell, L. D., Liu, Y., Torbenson, M. S., Unalp‐Arida, A., et al. (2005) · Hepatology · doi:10.1002/hep.20701 · Cited by 10,791 · see citing works
Chalasani, N., Younossi, Z., Lavine, J. E., Charlton, M., Cusi, K., Rinella, M., Harrison, S. A., Brunt, E. M., & Sanyal, A. J. (2018) · Hepatology · doi:10.1002/hep.29367 · Cited by 7,239 · see citing works
Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention
Younossi, Z., Anstee, Q. M., Marietti, M., Hardy, T., Henry, L., Eslam, M., George, J., & Bugianesi, E. (2018) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2017.109 · Cited by 5,249 · see citing works
Pioglitazone, Vitamin E, or Placebo for Nonalcoholic Steatohepatitis
Sanyal, A. J., Chalasani, N., Kowdley, K. V., McCullough, A., Diehl, A. M., Bass, N. M., Neuschwander-Tetri, B. A., Lavine, J. E., Tonascia, J., Unalp, A., et al. (2010) · New England Journal of Medicine · doi:10.1056/nejmoa0907929 · Cited by 3,327 · see citing works
Hepatic Stellate Cells: Protean, Multifunctional, and Enigmatic Cells of the Liver
Friedman, S. L. (2008) · Physiological Reviews · doi:10.1152/physrev.00013.2007 · Cited by 2,842 · see citing works
Neuschwander-Tetri, B. A., Loomba, R., Sanyal, A. J., Lavine, J. E., Van Natta, M. L., Abdelmalek, M. F., Chalasani, N., Dasarathy, S., Diehl, A. M., Hameed, B., et al. (2015) · The Lancet · doi:10.1016/s0140-6736(14)61933-4 · Cited by 2,237 · see citing works
Dulai, P. S., Singh, S., Patel, J., Soni, M., Prokop, L. J., Younossi, Z., Sebastiani, G., Ekstedt, M., Hagstrom, H., Nasr, P., et al. (2017) · Hepatology · doi:10.1002/hep.29085 · Cited by 1,965 · see citing works
TLR4 enhances TGF-β signaling and hepatic fibrosis
Seki, E., De Minicis, S., Österreicher, C. H., Kluwe, J., Osawa, Y., Brenner, D. A., & Schwabe, R. F. (2007) · Nature Medicine · doi:10.1038/nm1663 · Cited by 1,942 · see citing works
Self-citationA placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis
Belfort, R., Harrison, S. A., Brown, K., Darland, C., Finch, J., Hardies, J., Balas, B., Gastaldelli, A., Tio, F., Pulcini, J., et al. (2006) · New England Journal of Medicine · doi:10.1056/nejmoa060326 · Cited by 1,827 · see citing works
Boursier, J., Mueller, O., Barret, M., Machado, M., Fizanne, L., Araujo‐Perez, F., Guy, C. D., Seed, P. C., Rawls, J. F., David, L. A., et al. (2016) · Hepatology · doi:10.1002/hep.28356 · Cited by 1,483 · see citing works
Brunt, E. M., Kleiner, D. E., Wilson, L. A., Belt, P., & Neuschwander-Tetri, B. A. (2011) · Hepatology · doi:10.1002/hep.24127 · Cited by 1,251 · see citing works
Loomba, R., Seguritan, V., Li, W., Long, T., Klitgord, N., Bhatt, A., Dulai, P. S., Caussy, C., Bettencourt, R., Highlander, S. K., et al. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.04.001 · Cited by 1,123 · see citing works
Taylor, R. S., Taylor, R. J., Bayliss, S., Hagström, H., Nasr, P., Schattenberg, J. M., Ishigami, M., Toyoda, H., Wai-Sun Wong, V., Peleg, N., et al. (2020) · Gastroenterology · doi:10.1053/j.gastro.2020.01.043 · Cited by 1,069 · see citing works
The role of the gut microbiota in NAFLD
Leung, C., Rivera, L., Furness, J. B., & Angus, P. W. (2016) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2016.85 · Cited by 1,020 · see citing works
Nonalcoholic Steatohepatitis: Definition and Pathology
Brunt, E. M. (2001) · Seminars in Liver Disease · doi:10.1055/s-2001-12925 · Cited by 915 · see citing works
Vilar-Gomez, E., Calzadilla-Bertot, L., Wai-Sun Wong, V., Castellanos, M., Aller-de la Fuente, R., Metwally, M., Eslam, M., Gonzalez-Fabian, L., Alvarez-Quiñones Sanz, M., Conde-Martin, A. F., et al. (2018) · Gastroenterology · doi:10.1053/j.gastro.2018.04.034 · Cited by 806 · see citing works
Tsuchida, T., Lee, Y. A., Fujiwara, N., Ybanez, M., Allen, B., Martins, S., Fiel, M. I., Goossens, N., Chou, H.-I., Hoshida, Y., et al. (2018) · Journal of Hepatology · doi:10.1016/j.jhep.2018.03.011 · Cited by 583 · see citing works
Pathogenesis of Nonalcoholic Steatohepatitis
Machado, M. V., & Diehl, A. M. (2016) · Gastroenterology · doi:10.1053/j.gastro.2016.02.066 · Cited by 541 · see citing works
A diet-induced animal model of non-alcoholic fatty liver disease and hepatocellular cancer
Asgharpour, A., Cazanave, S. C., Pacana, T., Seneshaw, M., Vincent, R., Banini, B. A., Kumar, D. P., Daita, K., Min, H.-K., Mirshahi, F., et al. (2016) · Journal of Hepatology · doi:10.1016/j.jhep.2016.05.005 · Cited by 538 · see citing works
Animal models of nonalcoholic fatty liver disease
Hebbard, L., & George, J. (2010) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2010.191 · Cited by 495 · see citing works
Richardson, M. M., Jonsson, J. R., Powell, E. E., Brunt, E. M., Neuschwander–Tetri, B. A., Bhathal, P. S., Dixon, J. B., Weltman, M. D., Tilg, H., Moschen, A. R., et al. (2007) · Gastroenterology · doi:10.1053/j.gastro.2007.05.012 · Cited by 482 · see citing works
The Human Microbiome and Obesity: Moving beyond Associations
Maruvada, P., Leone, V., Kaplan, L. M., & Chang, E. B. (2017) · Cell Host & Microbe · doi:10.1016/j.chom.2017.10.005 · Cited by 468 · see citing works
Charlton, M., Krishnan, A., Viker, K., Sanderson, S. O., Cazanave, S. C., McConico, A. L., Masuoko, H., & Gores, G. J. (2011) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00145.2011 · Cited by 444 · see citing works
Promotion of cholangiocarcinoma growth by diverse cancer-associated fibroblast subpopulations
Affo, S., Nair, A., Brundu, F., Ravichandra, A., Bhattacharjee, S., Matsuda, M., Chin, L., Filliol, A., Wen, W., Song, X., et al. (2021) · Cancer Cell · doi:10.1016/j.ccell.2021.03.012 · Cited by 416 · see citing works
Self-citationLeptin is essential for the hepatic fibrogenic response to chronic liver injury
Leclercq, I. A., Farrell, G. C., Schriemer, R., & Robertson, G. R. (2002) · Journal of Hepatology · doi:10.1016/s0168-8278(02)00102-2 · Cited by 407 · see citing works
Preclinical models of non-alcoholic fatty liver disease
Santhekadur, P. K., Kumar, D. P., & Sanyal, A. J. (2018) · Journal of Hepatology · doi:10.1016/j.jhep.2017.10.031 · Cited by 380 · see citing works
Kohli, R., Kirby, M., Xanthakos, S. A., Softic, S., Feldstein, A. E., Saxena, V., Tang, P., Miles, L., Miles, M. V., Balistreri, W. F., et al. (2010) · Hepatology · doi:10.1002/hep.23797 · Cited by 377 · see citing works
Farrell, G., Schattenberg, J. M., Leclercq, I., Yeh, M. M., Goldin, R., Teoh, N., & Schuppan, D. (2019) · Hepatology · doi:10.1002/hep.30333 · Cited by 313 · see citing works
Klebig, M. L., Wilkinson, J. E., Geisler, J. G., & Woychik, R. P. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.11.4728 · Cited by 290 · see citing works
Therapeutic pipeline in nonalcoholic steatohepatitis
Vuppalanchi, R., Noureddin, M., Alkhouri, N., & Sanyal, A. J. (2021) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-020-00408-y · Cited by 278 · see citing works
Mouse models of the metabolic syndrome
Kennedy, A. J., Ellacott, K. L. J., King, V. L., & Hasty, A. H. (2010) · Disease Models & Mechanisms · doi:10.1242/dmm.003467 · Cited by 265 · see citing works
Giles, D. A., Moreno‐Fernandez, M. E., Stankiewicz, T. E., Graspeuntner, S., Cappelletti, M., Wu, D. X.-Y., Mukherjee, R., Chan, C. C., Lawson, M. J., Klarquist, J. S., et al. (2017) · Nature Medicine · doi:10.1038/nm.4346 · Cited by 238 · see citing works
Pathology of fatty liver disease
Brunt, E. M. (2007) · Modern Pathology · doi:10.1038/modpathol.3800680 · Cited by 238 · see citing works
Animal Models of Nonalcoholic Steatohepatitis: Eat, Delete, and Inflame
Ibrahim, S. H., Hirsova, P., Malhi, H., & Gores, G. J. (2016) · Digestive Diseases and Sciences · doi:10.1007/s10620-015-3977-1 · Cited by 218 · see citing works
Im, Y. R., Hunter, H., de Gracia Hahn, D., Duret, A., Cheah, Q., Dong, J., Fairey, M., Hjalmarsson, C., Li, A., Lim, H. K., et al. (2021) · Hepatology · doi:10.1002/hep.31897 · Cited by 195 · see citing works
Hoang, S. A., Oseini, A. M., Feaver, R. E., Cole, B. K., Asgharpour, A., Vincent, R. J., Siddiqui, M. S., Lawson, M. J., Day, N., Taylor, J. M., et al. (2019) · Scientific Reports · doi:10.1038/s41598-019-48746-5 · Cited by 191 · see citing works
Melanocortin 4 Receptor–Deficient Mice as a Novel Mouse Model of Nonalcoholic Steatohepatitis
Itoh, M., Suganami, T., Nakagawa, N., Tanaka, M., Yamamoto, Y., Kamei, Y., Terai, S., Sakaida, I., & Ogawa, Y. (2011) · American Journal Of Pathology · doi:10.1016/j.ajpath.2011.07.014 · Cited by 167 · see citing works
Pathogenesis of NASH: the Impact of Multiple Pathways
Noureddin, M., & Sanyal, A. J. (2018) · Current Hepatology Reports · doi:10.1007/s11901-018-0425-7 · Cited by 135 · see citing works
Modeling the Western Diet for Preclinical Investigations
Hintze, K. J., Benninghoff, A. D., Cho, C. E., & Ward, R. E. (2018) · Advances in Nutrition · doi:10.1093/advances/nmy002 · Cited by 112 · see citing works
A simple and rapid method to assay triacylglycerol in cells and tissues
Schwartz, D. M., & Wolins, N. E. (2007) · Journal of Lipid Research · doi:10.1194/jlr.d700017-jlr200 · Cited by 94 · see citing works
Tsai, M., Liu, Y.-Y., Lin, C., Wang, C., Wu, Y., Yong, C., Chen, K., Chuah, S., Yao, C., Huang, P., et al. (2020) · Nutrients · doi:10.3390/nu12030820 · Cited by 92 · see citing works
The genetic epidemiology of melanocortin 4 receptor variants
Loos, R. J. F. (2011) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2011.01.033 · Cited by 87 · see citing works
Caviglia, J. M., Yan, J., Jang, M. K., Gwak, G., Affò, S., Yu, L., Olinga, P., Friedman, R. A., Chen, X., & Schwabe, R. F. (2017) · Hepatology · doi:10.1002/hep.29627 · Cited by 81 · see citing works
Self-citationObesity-associated mutations in the human melanocortin-4 receptor gene
MacKenzie, R. G. (2005) · Peptides · doi:10.1016/j.peptides.2005.03.064 · Cited by 70 · see citing works
Exacerbation of dietary steatohepatitis and fibrosis in obese, diabetic KK–Ay mice
Okumura, K., Ikejima, K., Kon, K., Abe, W., Yamashina, S., ENOMOTO, N., TAKEI, Y., & Sato, N. (2006) · Hepatology Research · doi:10.1016/j.hepres.2006.07.009 · Cited by 56 · see citing works
Towards a definite mouse model of NAFLD
Castro, R. E., & Diehl, A. M. (2018) · Journal of Hepatology · doi:10.1016/j.jhep.2018.05.002 · Cited by 28 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH)
Wang, S., & Friedman, S. L. (2023) · Science Translational Medicine · doi:10.1126/scitranslmed.adi0759 · Cited by 158 · see citing works
The genetic background shapes the susceptibility to mitochondrial dysfunction and NASH progression
Benegiamo, G., von Alvensleben, G., Rodríguez-López, S., Goeminne, L. J. E., Bachmann, A., Morel, J., Broeckx, E., Ma, J. Y., Carreira, V., Youssef, S. A., et al. (2023) · The Journal of Experimental Medicine · doi:10.1084/jem.20221738 · Cited by 52 · see citing works
Leslie, J., Krishnamurthy, K. A., Gopalsamy, I. K., Inácio, P., Huch, M., Gallage, S., Oakley, F., & Vacca, M. (2026) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-025-01162-9 · Cited by 25 · see citing works
Zhang, C., Tong, Q., Liu, K., Mao, T., Song, Y., Qu, Y., Chen, X., & Qiu, Z. (2024) · Phytomedicine · doi:10.1016/j.phymed.2024.155703 · Cited by 20 · see citing works
Bednarski, T. K., Rahim, M., Hasenour, C. M., Banerjee, D. R., Trenary, I. A., Wasserman, D. H., & Young, J. D. (2024) · Journal of Lipid Research · doi:10.1016/j.jlr.2024.100558 · Cited by 15 · see citing works
Rodríguez-Ramiro, I., Pastor-Fernández, A., López-Aceituno, J. L., García-Domínguez, E., Sierra-Ramírez, A., Valverde, Á. M., Martínez-Pastor, B., Efeyan, A., Gómez-Cabrera, M., Viña, J., et al. (2023) · Free Radical Biology & Medicine · doi:10.1016/j.freeradbiomed.2023.11.019 · Cited by 13 · see citing works
Zou, X., & Brigstock, D. R. (2024) · Biomedicines · doi:10.3390/biomedicines12122848 · Cited by 10 · see citing works
Shi, Q., Fan, X., Yang, M., Tang, T., Wang, R., Li, P., & Qi, K. (2024) · Food Frontiers · doi:10.1002/fft2.339 · Cited by 3 · see citing works
Mouse Models for the Study of Liver Fibrosis Regression In Vivo and Ex Vivo
Schönke, M., & Rensen, P. C. N. (2024) · Journal of Clinical and Translational Hepatology · doi:10.14218/jcth.2024.00212 · Cited by 3 · see citing works
FGF1 orchestrates circadian hepatic triglyceride secretion
Sermikli, B. P., Liu, S., Kim, K., Hases, L., van Zutphen, T., Untereiner, A. A., Torres, J., He, M., Crossley, L., Dai, Y. D., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-70849-7 · Cited by 2 · see citing works
Altvater, E. E., Kojh, D., Huang, R., & Caviglia, J. M. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.09.25.678670 · Cited by 2 · see citing works
Self-citationMouse Model of Metabolic Dysfunction-Associated Steatotic Liver Disease with Fibrosis
Khoj, D., Huang, R. S., Altvater, E. E., Ishfaq, Z. N., Jiang, X., Axen, K. V., & Caviglia, J. M. (2025) · Journal of Visualized Experiments · doi:10.3791/68294 · Cited by 2 · see citing works
Self-citationBiomarkers of Hyperthermia in Male Wistar Rats: A Comprehensive Review
Kumari, A., Kumari, A., Prasad, M. K., Kumari, B., Kumar, N., & Sinha, R. K. (2025) · International Journal of Agricultural and Applied Sciences · doi:10.52804/ijaas2025.6217
Features of the gut microbiome in mice with polygenic disorders of energy metabolism
Novikova, N. S., Murovets, V. O., Леонидовна, С. А., Сергеевич, Г. Н., Sozontov, E. A., Alferova, L. S., Karaseva, A. B., Zolotarev, V. A., & Ермоленко, Е. И. (2026) · Journal of microbiology epidemiology immunobiology · doi:10.36233/0372-9311-830
- Authors
- St. Rose, K., Yan, J., Xu, F., Williams, J., Dweck, V., Saxena, D., Schwabe, R. F., & Caviglia, J. M.
- Affiliations
- Department of Health and Nutrition Sciences,Brooklyn College,CUNY,New York,New York,USA
- Nantong University (CN)
- New York University (US)
- City University of New York (US)
- Columbia University (US)
- Venue
- Hepatology Communications
- Published
- 2022-08-03
- Volume
- 6
- Issue
- 10
- Pages
- 2676-2688
- ISSN
- 2471-254X (ISSN-L)
- PMC
- PMC9512466
- OpenAlex
- W4289731779
- Cited by
- 14
- References
- 46
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 5 · 2023: 3
- FWCI
- 1.98
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Hepatology Communications (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (NSFC81300346)
- National Institute on Aging (R01AG068857)
- National Cancer Institute (R01CA206105, K22CA178098, R01CA262424, P30CA013696)
- National Institute of Diabetes and Digestive and Kidney Diseases (R03DK101863, R01DK128955, P30DK132710)
- National Institute of Dental and Craniofacial Research (R01DE025992)
- 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
- nonalcoholic steatohepatitis, non-alcoholic fatty liver disease, mouse model, hyperphagia, obesity, Western diet, high fructose corn syrup, impaired glucose tolerance, gut dysbiosis, liver fibrosis, hepatic gene expression, preclinical drug testing
- MeSH terms
- Animals, Disease Models, Animal, Fibrosis, Fructose, Humans, Mice, Inbred C57BL, Obesity, Water, Mice, Non-alcoholic Fatty Liver Disease
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
