Animal models of non‐alcoholic fatty liver disease: current perspectives and recent advances
Open accessAbstract
Non‐alcoholic fatty liver disease ( NAFLD ) is a continuous spectrum of diseases characterized by excessive lipid accumulation in hepatocytes. NAFLD progresses from simple liver steatosis to non‐alcoholic steatohepatitis and, in more severe cases, to liver fibrosis, cirrhosis, and hepatocellular carcinoma ( HCC ). Because of its growing worldwide prevalence, various animal models that mirror both the histopathology and the pathophysiology of each stage of human NAFLD have been developed. The selection of appropriate animal models continues to be one of the key questions faced in this field. This review presents a critical analysis of the histopathology and pathogenesis of NAFLD , the most frequently used and recently developed animal models for each stage of NAFLD and NAFLD ‐induced HCC , the main mechanisms involved in the experimental pathogenesis of NAFLD in different animal models, and a brief summary of recent therapeutic targets found by the use of animal models. Integrating the data from human disease with those from animal studies indicates that, although current animal models provide critical guidance in understanding specific stages of NAFLD pathogenesis and progression, further research is necessary to develop more accurate models that better mimic the disease spectrum, in order to provide both increased mechanistic understanding and identification/testing of novel therapeutic approaches. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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?
Induction of MASLD in vitro using FFAs leads to pronounced and quantitatively measurable lipid accumulation in cell lines within 24-72 h, contrasting with animal models where HFD induces steatosis in 8-16 weeks, steatohepatitis in 16-36 weeks, and fibrosis/cirrhosis in 24-52 weeks or more.
“Induction of MASLD in vitro using free fatty acids leads to a pronounced and quantitatively measurable accumulation of lipids in cell lines within 24–72 h [29].”
From The HepG2 Cell Line as a Model for Studying Metabolic Dysfunction-Associated Steatotic Liver Disease (2026) · cites this paper as [56]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredHigh-fat diet-induced MAFLD shares similar histologic and pathogenic characteristics with clinical MAFLD, featuring concomitant obesity and insulin resistance.
“High‐fat diet‐induced MAFLD shares similar histologic and pathogenic characteristics with clinical MAFLD, featuring concomitant obesity and IR (Lau et al., 2017).”
From <i>Akkermansia muciniphila</i> alleviates <scp>high‐fat‐diet</scp> ‐related metabolic‐associated fatty liver disease by modulating gut microbiota and bile acids (2023) · cites this paper as Lau et al., 2017
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
Steatohepatitis: A tale of two “hits”?
Day, C. P., & James, O. F. W. (1998) · Gastroenterology · doi:10.1016/s0016-5085(98)70599-2 · Cited by 4,285 · cited 1× · see citing works
“The progressive transition from steatosis to NASH was initially explained by a two-hit hypothesis [32], although recent studies have proposed a modified ‘multiple-hit’ model.”
ResultNonalcoholic Steatohepatitis: A Proposal for Grading and Staging The Histological Lesions
Brunt, E. M., Janney, C. G., Di Bisceglie, A. M., Neuschwander-Tetri, B. A., & Bacon, B. R. (1999) · American Journal of Gastroenterology · doi:10.1111/j.1572-0241.1999.01377.x · Cited by 3,907 · cited 1× · see citing works
“In severe cases, steatosis can occupy the entire acinus [10].”
BackgroundEvolution of inflammation in nonalcoholic fatty liver disease: The multiple parallel hits hypothesis
Tilg, H., & Moschen, A. R. (2010) · Hepatology · doi:10.1002/hep.24001 · Cited by 2,548 · cited 1× · see citing works
“This is followed by a series of hits, including oxidative stress, proinflammatory cytokine-mediated hepatocyte injury, altered lipid partitioning and hepatoxicity mediated by FFAs, abnormal intrahepatic cholesterol loading, hyperinsulinaemia, hyperleptinaemia, and hypoadiponectinaemia [33,34].”
BackgroundNonalcoholic Fatty Liver Disease: From Steatosis to Cirrhosis
Farrell, G. C., & Larter, C. Z. (2006) · Hepatology · doi:10.1002/hep.20973 · Cited by 2,413 · cited 1× · see citing works
“The development of steatosis is followed by progression to NASH in one-third of patients with NAFLD [27].”
BackgroundNonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities
Sanyal, A. J., Campbell–Sargent, C., Mirshahi, F., Rizzo, W. B., Contos, M. J., Sterling, R. K., Luketic, V. A., Shiffman, M. L., & Clore, J. N. (2001) · Gastroenterology · doi:10.1053/gast.2001.23256 · Cited by 2,078 · cited 1× · see citing works
“Studies have found a strong association between the degree of oxidative stress and the severity of NASH [35], and also the presence of biological markers of oxidative stress, in both patients and animal models of steatohepatitis [36,37].”
BackgroundAssociation of nonalcoholic fatty liver disease with insulin resistance
Marchesini, G., Brizi, M., Morselli‐Labate, A. M., Bianchi, G. P., Bugianesi, E., McCullough, A. J., Forlani, G., & Melchionda, N. (1999) · The American Journal of Medicine · doi:10.1016/s0002-9343(99)00271-5 · Cited by 1,564 · cited 1× · see citing works
“NAFLD has a strong association with metabolic abnormalities such as obesity [1,2], insulin resistance (IR) [3,4], fasting hyperglycaemia, dyslipidaemia, and altered adipokine profiles [4].”
BackgroundNonalcoholic Fatty Liver Disease and Hepatocellular Carcinoma: A Weighty Connection
Starley, B. Q., Calcagno, C. J., & Harrison, S. A. (2010) · Hepatology · doi:10.1002/hep.23594 · Cited by 1,340 · cited 2× · see citing works
“NASH with fibrosis or cirrhosis increases the risk of developing hepatocellular carcinoma (HCC) [7].”
BackgroundFatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with analysis of risk factors.
Wanless, I. R., & Lentz, J. S. (1990) · Hepatology · doi:10.1002/hep.1840120505 · Cited by 1,191 · cited 1× · see citing works
“NAFLD has a strong association with metabolic abnormalities such as obesity [1,2], insulin resistance (IR) [3,4], fasting hyperglycaemia, dyslipidaemia, and altered adipokine profiles [4].”
BackgroundLiver fibrosis in overweight patients
Ratziu, V., Giral, P., Charlotte, F., Bruckert, É., Thibault, V., Theodorou, I. D., Khalil, L., Turpin, G., Opolon, P., & Poynard, T. (2000) · Gastroenterology · doi:10.1016/s0016-5085(00)70364-7 · Cited by 969 · cited 1× · see citing works
“NAFLD has a strong association with metabolic abnormalities such as obesity [1,2], insulin resistance (IR) [3,4], fasting hyperglycaemia, dyslipidaemia, and altered adipokine profiles [4].”
BackgroundGaggini, M., Morelli, M., Buzzigoli, E., DeFronzo, R. A., Bugianesi, E., & Gastaldelli, A. (2013) · Nutrients · doi:10.3390/nu5051544 · Cited by 824 · cited 1× · see citing works
“NAFLD has a strong association with metabolic abnormalities such as obesity [1,2], insulin resistance (IR) [3,4], fasting hyperglycaemia, dyslipidaemia, and altered adipokine profiles [4].”
BackgroundYang, S. Q., Lin, H. Z., Lane, M. D., Clemens, M. G., & Diehl, A. M. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.6.2557 · Cited by 808 · cited 2× · see citing works
“Secondary insults are also required to trigger steatohepatitis, such as an MCD diet, an HFD, small doses of lipopolysaccharide endotoxin [23], ethanol, or hepatic ischaemia–reperfusion challenge [11].”
BackgroundPathogenesis of non-alcoholic fatty liver disease
Dowman, J. K., Tomlinson, J., & Newsome, P. N. (2009) · QJM · doi:10.1093/qjmed/hcp158 · Cited by 742 · cited 11× · see citing works
“In the context of FFA load, mitochondrial β-oxidation can become overwhelmed, reesulting in an increase in reactive oxygen species (ROS) production [6] (Figure 1).”
BackgroundInfluentialLong-Term Follow-Up of Patients With Nonalcoholic Fatty Liver
Rafiq, N., Bai, C., Fang, Y. H., Srishord, M. K., McCullough, A. J., Gramlich, T., & Younossi, Z. M. (2008) · Clinical Gastroenterology and Hepatology · doi:10.1016/j.cgh.2008.11.005 · Cited by 729 · see citing works
Mouse models in non‐alcoholic fatty liver disease and steatohepatitis research
Anstee, Q. M., & Goldin, R. D. (2006) · International Journal of Experimental Pathology · doi:10.1111/j.0959-9673.2006.00465.x · Cited by 714 · cited 5× · see citing works
“Obesity, and particularly IR, are tightly associated with the genesis of NAFLD [11,13].”
BackgroundInfluentialARAYA, J., RODRIGO, R., VIDELA, L. A., THIELEMANN, L., ORELLANA, M., PETTINELLI, P., & PONIACHIK, J. (2004) · Clinical Science · doi:10.1042/cs20030326 · Cited by 700 · cited 1× · see citing works
“Second, IR-associated hyperinsulinaemia and hyperglycaemia promote hepatic de novo lipid synthesis via upregulation of the membrane-bound transcription factor sterol regulatory element-binding protein-1c (SREBP-1c) and carbohydrate response element-binding protein (ChREBP), respectively (Figure 1) [16,17].”
BackgroundHepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas
Horie, Y., Suzuki, A., Kataoka, E., Sasaki, T., Hamada, K., Sasaki, J., Mizuno, K., Hasegawa, G., Kishimoto, H., Iizuka, M., et al. (2004) · Journal of Clinical Investigation · doi:10.1172/jci20513 · Cited by 699 · cited 1× · see citing works
“Phosphatase and tensin homolog (PTEN) is a tumour suppressor because of its lipid phosphatase activity, and is mutated in many human cancers [65].”
BackgroundWolf, M. J., Adili, A., Piotrowitz, K., Abdullah, Z., Boege, Y., Stemmer, K., Ringelhan, M., Simonavicius, N., Egger, M., Wohlleber, D., et al. (2014) · Cancer Cell · doi:10.1016/j.ccell.2014.09.003 · Cited by 678 · cited 1× · see citing works
“5%, as compared with 25% in CD-HFD mice [61].”
BackgroundIncreased overall mortality and liver-related mortality in non-alcoholic fatty liver disease
Ong, J. P., Pitts, A., & Younossi, Z. M. (2008) · Journal of Hepatology · doi:10.1016/j.jhep.2008.06.018 · Cited by 636 · see citing works
From NAFLD to NASH to cirrhosis—new insights into disease mechanisms
Wree, A., Broderick, L., Canbay, A. E., Hoffman, H. M., & Feldstein, A. E. (2013) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2013.149 · Cited by 608 · cited 1× · see citing works
“Its worldwide prevalence continues to increase with the growing epidemic of obesity and insulin resistance, and it is becoming the most common cause of chronic liver disease [5].”
BackgroundAnimal models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis
Takahashi, Y. (2012) · World Journal of Gastroenterology · doi:10.3748/wjg.v18.i19.2300 · Cited by 554 · cited 2× · see citing works
“5%) diet also showed greater steatosis, inflammation, hepatocellular ballooning, and fibrosis [31,49].”
BackgroundA 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 · cited 6× · see citing works
“This review will summarize the current and most frequently used animal models for each stage of NAFLD: (1) non-alcoholic fatty liver (simple steatosis); (2) NASH; and (3) NASH-associated HCC.”
BackgroundInfluentialLipid-induced oxidative stress causes steatohepatitis in mice fed an atherogenic diet
Matsuzawa, N., Takamura, T., Kurita, S., Misu, H., Ota, T., Ando, H., Yokoyama, M., Honda, M., Zen, Y., Nakanuma, Y., et al. (2007) · Hepatology · doi:10.1002/hep.21874 · Cited by 516 · cited 1× · see citing works
“5%) diet also showed greater steatosis, inflammation, hepatocellular ballooning, and fibrosis [31,49].”
BackgroundCholine metabolism provides novel insights into nonalcoholic fatty liver disease and its progression
Corbin, K. D., & Zeisel, S. H. (2011) · Current Opinion in Gastroenterology · doi:10.1097/mog.0b013e32834e7b4b · Cited by 502 · cited 1× · see citing works
“Depriving animals of choline alone impairs hepatic very-low-density lipoprotein (VLDL) secretion and results in hepatosteatosis, oxidative stress, liver cell death, and changes in cytokines and adipocytokines [42], but causes only slight hepatic inflammation and fibrosis.”
BackgroundInsulin resistance associated to obesity: the link TNF-alpha
Nieto-Vázquez, I., Fernández‐Veledo, S., Kramer, D., Vila‐Bedmar, R., García‐Guerra, L., & Lorenzo, M. (2008) · Archives of Physiology and Biochemistry · doi:10.1080/13813450802181047 · Cited by 475 · cited 3× · see citing works
“IR leads to an increase in the liver triglyceride level and ultimately liver steatosis through various mechanisms [14].”
BackgroundRinella, M. E., & Green, R. M. (2003) · Journal of Hepatology · doi:10.1016/j.jhep.2003.09.020 · Cited by 462 · cited 1× · see citing works
“Instead of being obese, mice fed an MCD diet show significant weight loss, cachexia, no IR, and low serum insulin, fasting glucose, leptin and triglyceride levels [47].”
BackgroundHistopathology of nonalcoholic fatty liver disease
Brunt, E. M. (2010) · World Journal of Gastroenterology · doi:10.3748/wjg.v16.i42.5286 · Cited by 448 · cited 3× · see citing works
“Lobular inflammation is followed by infiltration of affected areas by innate immune cells [28,29].”
BackgroundPathogenesis of steatohepatitis
Day, C. P. (2002) · Best Practice & Research Clinical Gastroenterology · doi:10.1053/bega.2002.0333 · Cited by 430 · cited 1× · see citing works
“Obesity, and particularly IR, are tightly associated with the genesis of NAFLD [11,13].”
BackgroundModel of nonalcoholic steatohepatitis
Lieber, C. S., Leo, M. A., Mak, K. M., Xu, Y., Cao, Q., Ren, C., Ponomarenko, A. N., & DeCarli, L. M. (2004) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/79.3.502 · Cited by 425 · cited 1× · see citing works
“Weight change, however, was the same in both HFD and control rats [19].”
BackgroundLeptin 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 · cited 2× · see citing works
“However, unlike db/db mice, ob/ob mice are resistant to hepatic fibrosis, owing to hepatic fibrosis requiring leptin [24].”
BackgroundMitochondria in Steatohepatitis
Pessayre, D., Berson, A., Fromenty, B., & Mansouri, A. (2001) · Seminars in Liver Disease · doi:10.1055/s-2001-12929 · Cited by 390 · cited 1× · see citing works
“Under continuous oxidative stress, an imbalance between ROS and the antioxidant capacity of the cell leads to lipid peroxidation and ultimately cellular damage [39].”
BackgroundPortal chronic inflammation in nonalcoholic fatty liver disease (NAFLD)
Brunt, E. M., Kleiner, D. E., Wilson, L., Ünalp, A., Behling, C. A., Lavine, J. E., & Neuschwander‐Tetri, B. A. (2008) · Hepatology · doi:10.1002/hep.22724 · Cited by 388 · see citing works
Experimental mouse models for hepatocellular carcinoma research
Heindryckx, F., Colle, I., & van Vlierberghe, H. (2009) · International journal of experimental pathology (Print) · doi:10.1111/j.1365-2613.2009.00656.x · Cited by 383 · cited 2× · see citing works
“Thus, this model is useful for understanding not only the pathogenesis of NASH, but also the progression of NASH to HCC. Combined genetic and chemical NAFLD-induced HCC Genetic obesity in db/db mice is a direct promoter of NASH-associated HCC development. db/db mice treated with the carcinogen diethylnitrosamine when…”
BackgroundMachado, M. V., Michelotti, G. A., Xie, G., Pereira, T. A., Boursier, J., Bohnic, B., Guy, C. D., & Diehl, A. M. (2015) · PLoS ONE · doi:10.1371/journal.pone.0127991 · Cited by 381 · cited 1× · see citing works
“Endoplasmic reticulum stress, oxidative stress and autophagocytic stress are all more active in MCD models than in other dietary models [46].”
BackgroundKohli, 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 · cited 2× · see citing works
“Humans consume a significant number of calories from fructose-rich foods, and this has been linked with the development of obesity and NASH [53].”
BackgroundFujii, M., Shibazaki, Y., Wakamatsu, K., Honda, Y., Kawauchi, Y., Suzuki, K., Arumugam, S., Watanabe, K., Ichida, T., Asakura, H., et al. (2013) · Medical Molecular Morphology · doi:10.1007/s00795-013-0016-1 · Cited by 355 · cited 1× · see citing works
“The model provides insights into the mechanisms linking metabolic disorder, NASH, and HCC [64].”
BackgroundDentin, R., Girard, J. R., & Postic, C. (2004) · Biochimie · doi:10.1016/j.biochi.2004.11.008 · Cited by 328 · cited 1× · see citing works
“Second, IR-associated hyperinsulinaemia and hyperglycaemia promote hepatic de novo lipid synthesis via upregulation of the membrane-bound transcription factor sterol regulatory element-binding protein-1c (SREBP-1c) and carbohydrate response element-binding protein (ChREBP), respectively (Figure 1) [16,17].”
BackgroundPresence and significance of microvesicular steatosis in nonalcoholic fatty liver disease
Tandra, S., Yeh, M. M., Brunt, E. M., Vuppalanchi, R., Cummings, O. W., Ünalp–Arida, A., Wilson, L., & Chalasani, N. (2010) · Journal of Hepatology · doi:10.1016/j.jhep.2010.11.021 · Cited by 328 · cited 1× · see citing works
“NAFLD is histologically diagnosed when accumulation occurs in >5% of hepatocytes [9].”
BackgroundStojsavljević, S. (2014) · World Journal of Gastroenterology · doi:10.3748/wjg.v20.i48.18070 · Cited by 325 · cited 1× · see citing works
“Both TNF-α and IL-6 affect adipokine levels, as they: (1) decrease the levels of adiponectin, which has anti-inflammatory, anti-atherogenic and anti-diabetic properties; and (2) increase leptin levels, resulting in perpetuation of the loop of chronic inflammation in obesity (Figure 1) [40,41].”
BackgroundSavard, C. E., Tartaglione, E. V., Kuver, R., Haigh, G. W., Farrell, G. C., Subramanian, S., Chait, A., Yeh, M. M., Quinn, L. S., & Ioannou, G. N. (2012) · Hepatology · doi:10.1002/hep.25789 · Cited by 297 · cited 4× · see citing works
“All of these features were more pronounced in HFHC mice than in HFD or HCD mice [52].”
BackgroundInfluentialIn Vitro and in Vivo Models of Non-Alcoholic Fatty Liver Disease (NAFLD)
Kanuri, G., & Bergheim, I. (2013) · International Journal of Molecular Sciences · doi:10.3390/ijms140611963 · Cited by 293 · cited 1× · see citing works
“Long-term feeding with a methionine-deficient diet caused more pronounced liver injury in DBA/2 J mice than in C57BL/6 mice, and caused hepatocarcinogenesis in DBA/2 J mice but not in C57BL/6 mice [48].”
BackgroundHistological assessment of non‐alcoholic fatty liver disease
Hübscher, S. G. (2006) · Histopathology · doi:10.1111/j.1365-2559.2006.02416.x · Cited by 292 · cited 1× · see citing works
“Simple hepatic steatosis encompasses fat droplet accumulation in hepatocytes [8].”
BackgroundSahai, A., Malladi, P., Pan, X., Paul, R., Melin-Aldana, H., Green, R. M., & Whitington, P. F. (2004) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00199.2004 · Cited by 290 · cited 2× · see citing works
“db/db mice fed an MCD diet show marked hepatic inflammation and fibrosis [25].”
BackgroundNon-alcoholic fatty liver disease pathogenesis: The present and the future
Petta, S., Muratore, C., & Craxı̀, A. (2009) · Digestive and Liver Disease · doi:10.1016/j.dld.2009.01.004 · Cited by 284 · cited 1× · see citing works
“Studies have found a strong association between the degree of oxidative stress and the severity of NASH [35], and also the presence of biological markers of oxidative stress, in both patients and animal models of steatohepatitis [36,37].”
BackgroundGeorge, J., Pera, N., Phung, N., Leclercq, I. A., Hou, J. Y., & Farrell, G. C. (2003) · Journal of Hepatology · doi:10.1016/s0168-8278(03)00376-3 · Cited by 247 · cited 2× · see citing works
“Studies have found a strong association between the degree of oxidative stress and the severity of NASH [35], and also the presence of biological markers of oxidative stress, in both patients and animal models of steatohepatitis [36,37].”
BackgroundSubramanian, S., Goodspeed, L., Wang, S., Kim, J. K., Zeng, L., Ioannou, G. N., Haigh, W. G., Yeh, M. M., Kowdley, K. V., O’Brien, K. D., et al. (2011) · Journal of Lipid Research · doi:10.1194/jlr.m016246 · Cited by 240 · cited 1× · see citing works
“have suggested that dietary cholesterol reduces VLDL synthesis and β-oxidation of fatty acids, and increases apoptosis and hepatic oxidative stress [51,52].”
BackgroundIII. Peroxisomal β-oxidation, PPARα, and steatohepatitis
Reddy, J. K. (2001) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.2001.281.6.g1333 · Cited by 235 · see citing works
Approach to the Pathogenesis and Treatment of Nonalcoholic Steatohepatitis
Medina, J., Fernández-Salazar, L. I., García-Buey, L., & Moreno‐Otero, R. (2004) · Diabetes Care · doi:10.2337/diacare.27.8.2057 · Cited by 229 · cited 2× · see citing works
“Additionally, genetic predisposition may be involved [15].”
BackgroundThe Role of Cytokines in Non-Alcoholic Fatty Liver Disease
Tilg, H. (2010) · Digestive Diseases · doi:10.1159/000282083 · Cited by 227 · cited 2× · see citing works
“An increase in the synthesis of proinflammatory cytokines, including TNF-α and interleukin (IL)-6, has been reported in NASH patients [40].”
BackgroundYilmaz, Y. N. (2012) · Alimentary Pharmacology & Therapeutics · doi:10.1111/apt.12046 · Cited by 217 · cited 1× · see citing works
“This is followed by a series of hits, including oxidative stress, proinflammatory cytokine-mediated hepatocyte injury, altered lipid partitioning and hepatoxicity mediated by FFAs, abnormal intrahepatic cholesterol loading, hyperinsulinaemia, hyperleptinaemia, and hypoadiponectinaemia [33,34].”
BackgroundImmune and inflammatory pathways in NASH
Ganz, M., & Szabó, G. (2013) · Hepatology International · doi:10.1007/s12072-013-9468-6 · Cited by 188 · cited 1× · see citing works
“Lobular inflammation is followed by infiltration of affected areas by innate immune cells [28,29].”
BackgroundEzetimibe improves high fat and cholesterol diet-induced non-alcoholic fatty liver disease in mice
Zheng, S., Hoos, L. M., Cook, J., Tetzloff, G. G., Davis, H. R., van Heek, M., & Hwa, J. J. (2008) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2008.01.045 · Cited by 163 · see citing works
Zhang, X., Han, J., Man, K., Li, X., Du, J., Chu, E. S., Go, M. Y. Y., Sung, J. J. �., & Yu, J. Q. (2015) · Journal of Hepatology · doi:10.1016/j.jhep.2015.09.005 · Cited by 156 · cited 1× · see citing works
“Cxcr3-knockout mice showed improved liver histology, a lower level of necroinflammation and reduced lipid peroxidation, suggesting that CXCR3 plays a pivotal role in NASH development in HFHF mouse models [54].”
BackgroundSelf-citationTrak-Smayra, V. E., Paradis, V., Massart, J., Nasser, S. M., Jebara, V. A., & Fromenty, B. (2011) · International Journal of Experimental Pathology · doi:10.1111/j.1365-2613.2011.00793.x · Cited by 147 · cited 3× · see citing works
“Prolonged calorie overconsumption (>1 month) may lead to slightly aggravated hepatic inflammation [22].”
BackgroundInfluentialLi, Y., Zalzala, M. H., Jadhav, K. S., Xu, Y., Kasumov, T., Yin, L., & Zhang, Y. (2016) · Hepatology · doi:10.1002/hep.28472 · Cited by 139 · cited 1× · see citing works
“In db/db mice, carboxylesterase 2 was demonstrated to be a novel triglyceride hydrolase involved in triglyceride homeostasis and NAFLD [69].”
BackgroundEccleston, H. B., Andringa, K. K., Betancourt, A. M., King, A. L., Mantena, S. K., Swain, T. M., Tinsley, H. N., Nolte, R. N., Nagy, T. R., Abrams, G. A., et al. (2010) · Antioxidants and Redox Signaling · doi:10.1089/ars.2010.3395 · Cited by 133 · cited 1× · see citing works
“HFD mice showed hepatic steatosis, as verified by the presence of increased liver triglyceride levels, hepatocyte ballooning, Mallory bodies, higher fasting serum glucose levels, and decreased adiponectin levels, suggesting hyperglycaemia and IR [20].”
BackgroundLarter, C. Z., Yeh, M. M., Williams, J., Bell-Anderson, K. S., & Farrell, G. C. (2008) · Journal of Hepatology · doi:10.1016/j.jhep.2008.03.026 · Cited by 133 · cited 1× · see citing works
“Serum alanine aminotransferase (ALT) levels also increase alongside with ballooning degeneration of hepatocytes [44].”
BackgroundHanda, P., Morgan‐Stevenson, V., Maliken, B. D., Nelson, J. E., Washington, S., Westerman, M. E., Yeh, M. M., & Kowdley, K. V. (2015) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00246.2015 · Cited by 132 · cited 1× · see citing works
“Unlike db/db mice fed a normal chow diet, db/db mice fed a chow diet supplemented with high iron showed hepatocellular ballooning, fibrogenesis, increased hepatic oxidative stress, inflammasome activation, hepatic inflammatory immune cell activation, and impaired hepatic mitochondrial fatty acid β-oxidation [57].”
BackgroundOng, J. P., Pitts, A., & Younossi, Z. M. (2008) · Journal of Hepatology · doi:10.1016/s0168-8278(08)60008-2 · Cited by 119 · see citing works
Lipid metabolism in hepatic steatosis
Bradbury, M. W., & Berk, P. D. (2004) · Clinics in Liver Disease · doi:10.1016/j.cld.2004.04.005 · Cited by 115 · cited 1× · see citing works
“Triglyceride accumulation occurs when the rate of import or synthesis of FFAs by hepatocytes exceeds the rate of export or catabolism [11,12].”
BackgroundCongenital leptin deficiency: diagnosis and effects of leptin replacement therapy
Paz-Filho, G., Mastronardi, C. A., Delibaşı, T., Wong, M., & Licinio, J. (2010) · Arquivos Brasileiros de Endocrinologia & Metabologia · doi:10.1590/s0004-27302010000800005 · Cited by 104 · cited 1× · see citing works
“However, congenital leptin deficiency and leptin resistance caused by gene mutations in obese humans are extremely rare [26], so db/db and ob/ob mouse models are limited in their ability to reflect the aetiology of human obesity, IR, and hepatic steatosis.”
BackgroundHCC Development Is Associated to Peripheral Insulin Resistance in a Mouse Model of NASH
De Minicis, S., Agostinelli, L., Rychlicki, C., Sorice, G. P., Saccomanno, S., Candelaresi, C., Giaccari, A., Trozzi, L., Pierantonelli, I., Mingarelli, E., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0097136 · Cited by 97 · cited 2× · see citing works
“HCC developed after 9 months of feeding [62].”
BackgroundFarrell, G. C., Mridha, A. R., Yeh, M. M., Arsov, T., Van Rooyen, D. M., Brooling, J., Nguyen, T., Heydet, D., Delghingaro‐Augusto, V., Nolan, C. J., et al. (2014) · Liver International · doi:10.1111/liv.12335 · Cited by 85 · cited 1× · see citing works
“These findings suggest that, although the levels of obesity are equal, the responses to obesity, including features of NASH, are strain-dependent [56].”
BackgroundWatanabe, S., Horie, Y., Kataoka, E., Sato, W., Dohmen, T., Ohshima, S., Goto, T., & Suzuki, A. (2007) · Journal of Gastroenterology and Hepatology · doi:10.1111/j.1440-1746.2006.04665.x · Cited by 76 · cited 7× · see citing works
“This review will summarize the current and most frequently used animal models for each stage of NAFLD: (1) non-alcoholic fatty liver (simple steatosis); (2) NASH; and (3) NASH-associated HCC.”
BackgroundInfluentialInsulin Inhibits Peroxisomal Fatty Acid Oxidation in Isolated Rat Hepatocytes
Hamel, F. G., Bennett, R. G., Upward, J. L., & Duckworth, W. C. (2001) · Endocrinology · doi:10.1210/endo.142.6.8178 · Cited by 50 · cited 7× · see citing works
“The HFD caused hepatic steatosis, and lipid concentrations were almost two-fold of those in control rats, owing to the increased dietary load of FFAs.”
BackgroundInfluentialActivation of CDK4 Triggers Development of Non-alcoholic Fatty Liver Disease
Jin, J., Valanejad, L., Nguyen, T. P., Lewis, K., Wright, M., Cast, A. E., Stock, L., Timchenko, L., & Timchenko, N. A. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.06.019 · Cited by 50 · cited 1× · see citing works
“A recent study using HFD mouse models found that activation of cyclin D3/cyclin-dependent kinase 4 is a key event in the development of NAFLD [68].”
BackgroundGlucagon-like peptide-1 analogue prevents nonalcoholic steatohepatitis in non-obese mice
Yamamoto, T. (2016) · World Journal of Gastroenterology · doi:10.3748/wjg.v22.i8.2512 · Cited by 48 · cited 1× · see citing works
“In db/db mice fed an MCD diet, administration of exendin-4 (a glucagon-like peptide-1 analogue) improved MCD diet-induced steatohepatitis and reduced hepatic triglyceride and FFA contents, suggesting that exendin-4 could be used for the treatment of non-obese patients with NASH [70].”
BackgroundOncogenic mutations and dysregulated pathways in obesity-associated hepatocellular carcinoma
Shen, J., Tsoi, H., Liang, Q., Chu, E., Liu, D.-B., Yu, C., Chan, T., Li, X., Sung, J. J. Y., Wong, V., et al. (2016) · Oncogene · doi:10.1038/onc.2016.162 · Cited by 39 · cited 1× · see citing works
“Findings from this mouse model suggest that obesity and NASH increase susceptibility to HCC development [67].”
BackgroundSelf-citationFakhoury-Sayegh, N., Trak-Smayra, V. E., Khazzaka, A., Esseily, F., Obeid, O., Lahoud-Zouein, M., & Younes, H. (2015) · Nutrition Research and Practice · doi:10.4162/nrp.2015.9.4.350 · Cited by 39 · cited 1× · see citing works
“The high-fat group had the highest body and liver weights, and the highest percentage of liver steatosis (40%) [21].”
BackgroundYamada, T., Obata, A., Kashiwagi, Y., Rokugawa, T., Matsushima, S., Hamada, T., Watabe, H., & Abe, K. (2016) · Magnetic Resonance Imaging · doi:10.1016/j.mri.2016.03.009 · Cited by 35 · cited 1× · see citing works
“However, mice fed a diet lacking both choline and methionine develop extensive hepatic inflammation as early as 2 weeks of feeding, and significant fibrosis after 6 weeks [11,43] (Figure 2C, D).”
BackgroundLee, S. J., Kang, J. H., Iqbal, W., & Kwon, O. (2015) · PLoS ONE · doi:10.1371/journal.pone.0120577 · Cited by 33 · cited 1× · see citing works
“Recent literature suggests that the progression of steatosis to steatohepatitis in MCD mouse models involves downregulation of proteins affecting methionine metabolism and oxidative stress, especially peroxiredoxin, which may participate in cellular defence against the development of hepatitis [45].”
BackgroundBell-Anderson, K. S., Aouad, L. J., Williams, H., Sanz, F. R., Phuyal, J. L., Larter, C. Z., Farrell, G. C., & Caterson, I. D. (2011) · International Journal of Obesity · doi:10.1038/ijo.2011.55 · Cited by 21 · cited 1× · see citing works
“Although its function has not been fully elucidated, ALMS1 may have a role in intracellular transport and appetite regulation [55].”
Background
Flagged first, then by citations
Cited by
Sorted by citations
The role of macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis
Kazankov, K., Jørgensen, S. M. D., Thomsen, K. L., Møller, H. J., Vilstrup, H., George, J., Schuppan, D., & Grønbæk, H. (2019) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-018-0082-x · Cited by 941 · see citing works
Pouwels, S., Sakran, N., Graham, Y. N. H., Leal, A., Pintar, T., Yang, W., Kassir, R., Singhal, R., Mahawar, K. K., & Ramnarain, D. (2022) · BMC Endocrine Disorders · doi:10.1186/s12902-022-00980-1 · Cited by 912 · see citing works
“In the recent years a lot of animal research has been conducted investigating the pathophysiology of NAFLD and NASH, mainly difference in dietary models (high fructose, high fat or methionine/ choline deficient diet (MCD) [10, 11].”
BackgroundPierantonelli, I., & Svegliati‐Baroni, G. (2018) · Transplantation · doi:10.1097/tp.0000000000002480 · Cited by 459 · see citing works
Animal Models of Nonalcoholic Fatty Liver Disease—A Starter’s Guide
Herck, M. A. V., Vonghia, L., & Francque, S. (2017) · Nutrients · doi:10.3390/nu9101072 · Cited by 389 · see citing works
“The excess supply of free fatty acids, directly via intake and via increased lipolysis, brings about triglyceride accumulation in the liver [26].”
BackgroundPreclinical 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
“Chow diet supplemented with a high iron load also induced major NAFLD features, such as hepatocellular ballooning, hepatic inflammatory immune cell activation, increased hepatic oxidative stress and impaired hepatic mitochondrial fatty acid b-oxidation and fibrogenesis in db/db mice.(55,31) Thus, iron may potentiate t…”
High fat diet-triggered non-alcoholic fatty liver disease: A review of proposed mechanisms
Lian, C.-Y., Zhai, Z., Li, Z., & Wang, L. (2020) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2020.109199 · Cited by 304 · see citing works
Beneficial Effects of Betaine: A Comprehensive Review
Arumugam, M. K., Paal, M. C., Donohue, T. M., Ganesan, M., Osna, N. A., & Kharbanda, K. K. (2021) · Biology · doi:10.3390/biology10060456 · Cited by 303 · see citing works
Widjaja, A. A., Singh, B. K., Adami, E., Viswanathan, S., Dong, J., D’Agostino, G. A., Ng, B., Lim, W., Tan, J., Paleja, B. S., et al. (2019) · Gastroenterology · doi:10.1053/j.gastro.2019.05.002 · Cited by 276 · see citing works
Gutiérrez‐Cuevas, J., Santos, A., & Armendáriz‐Borunda, J. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222111629 · Cited by 216 · see citing works
“While MAFLD is marked by macrovesicular steatosis without ballooned hepatocytes [59,61,62].”
BackgroundInfluentialMacrophage p38α promotes nutritional steatohepatitis through M1 polarization
Zhang, X., Fan, L., Wu, J., Xu, H., Leung, W. Y., Fu, K., Wu, J., Liu, K., Man, K., Yang, X., et al. (2019) · Journal of Hepatology · doi:10.1016/j.jhep.2019.03.014 · Cited by 205 · see citing works
Self-citationLi, W., Zhang, K., & Yang, H. (2018) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.8b02979 · Cited by 185 · see citing works
Non-alcoholic fatty liver disease in lean individuals
Albhaisi, S. A. M., Chowdhury, A., & Sanyal, A. J. (2019) · JHEP Reports · doi:10.1016/j.jhepr.2019.08.002 · Cited by 179 · see citing works
“Beta sitoterolemia is associated with increased uptake of dietary cholesterol and may lead to fatty liver disease; in animal models, cholesterol loading leads to more severe NAFLD.(46) The progression to steatohepatitis involves activation of cell stress signalling as a consequence of delivery of a toxic load of lipid…”
BackgroundNonalcoholic Fatty Liver Disease Induced by High-Fat Diet in C57bl/6 Models
Aydos, L. R., do Amaral, L. A., de Souza, R. S., Jacobowski, A. C., dos Santos, E. F., & Macedo, M. L. R. (2019) · Nutrients · doi:10.3390/nu11123067 · Cited by 170 · see citing works
Mitochondria, oxidative stress and nonalcoholic fatty liver disease: A complex relationship
Karkucińska‐Więckowska, A., Simões, I. C. M., Kalinowski, P., Lebiedzińska, M., Zieniewicz, K., Milkiewicz, P., Górska‐Ponikowska, M., Pinton, P., Malik, A. N., Krawczyk, M. J., et al. (2021) · European Journal of Clinical Investigation · doi:10.1111/eci.13622 · Cited by 165 · see citing works
Updates on Dietary Models of Nonalcoholic Fatty Liver Disease: Current Studies and Insights
Stephenson, K., Kennedy, L. L., Hargrove, L. A., Demieville, J., Thomson, J., Alpini, G. D., & Francis, H. (2017) · Gene Expression · doi:10.3727/105221617x15093707969658 · Cited by 142 · see citing works
Bruzzì, S., Sutti, S., Giudici, G., Burlone, M. E., Ramavath, N. N., Toscani, A., Bozzola, C., Schneider, P., Morello, E., Parola, M., et al. (2018) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2018.06.015 · Cited by 139 · see citing works
“Such an experimental model allows, in fact to reproduce NASH-associated fibrosis avoiding weight loss [29].”
Liver Organoids: Recent Developments, Limitations and Potential
Harrison, S. P., Baumgarten, S., Verma, R., Lunov, O., Dejneka, A., & Sullivan, G. J. (2021) · Frontiers in Medicine · doi:10.3389/fmed.2021.574047 · Cited by 141 · see citing works
Intestinal dysbiosis in nonalcoholic fatty liver disease (NAFLD): focusing on the gut–liver axis
Han, H. L., Jiang, Y., Wang, M., Melaku, M., Liu, L., Zhao, Y. M., Everaert, N., Yi, B., & Zhang, H. (2021) · Critical Reviews in Food Science and Nutrition · doi:10.1080/10408398.2021.1966738 · Cited by 130 · see citing works
Wu, W., Kaicen, W., Bian, X., Yang, L., Ding, S., Li, Y., Li, S., Zhuge, A., & Li, L. (2023) · Microbial Biotechnology · doi:10.1111/1751-7915.14293 · Cited by 129 · see citing works
Genetic and Diet-Induced Animal Models for Non-Alcoholic Fatty Liver Disease (NAFLD) Research
Flessa, C., Ansari, N. N., Kyrou, I., Leca, B. M., Lianou, M., Chatzigeorgiou, A., Kaltsas, G., Kassi, E. N., & Randeva, H. S. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232415791 · Cited by 129 · see citing works
“Overall, in HFD regimes, a higher percentage of cells enriched in fat is observed compared to other types of diets [10].”
BackgroundInfluentialPrill, S., Caddeo, A. M., Baselli, G., Jamialahmadi, O., Dongiovanni, P., Rametta, R., Kanebratt, K. P., Pujia, A., Pingitore, P., Mancina, R. M., et al. (2019) · Scientific Reports · doi:10.1038/s41598-019-47737-w · Cited by 123 · see citing works
Wang, N., Lu, X., Wang, J., Wang, H., Zhang, B., Zhao, W., & Zhang, J. (2023) · Analytical Chemistry · doi:10.1021/acs.analchem.2c05674 · Cited by 118 · see citing works
Jamwal, R., de la Monte, S. M., Ogasawara, K., Adusumalli, S., Barlock, B. J., & Akhlaghi, F. (2018) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.8b00159 · Cited by 117 · 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
Adori, C., Daraio, T., Kuiper, R., Barde, S., Horvathova, L., Yoshitake, T., Ihnatko, R., Valladolid-Acebes, I., Vercruysse, P., Wellendorf, A. M., et al. (2021) · Science Advances · doi:10.1126/sciadv.abg5733 · Cited by 105 · see citing works
Segovia-Miranda, F., Morales-Navarrete, H., Kücken, M., Moser, V., Seifert, S., Repnik, U., Rost, F., Brosch, M., Hendricks, A., Hinz, S., et al. (2019) · Nature Medicine · doi:10.1038/s41591-019-0660-7 · Cited by 109 · see citing works
Echeverría, F., Valenzuela, R., Espinosa, A., Bustamante, A., Álvarez, D., Gonzalez‐Mañán, D., Ortíz, M., Soto-Alarcón, S. A., & Videla, L. A. (2018) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2018.09.012 · Cited by 108 · see citing works
Tong, J., Li, D., Meng, H., Sun, D.-Y., Lan, X.-T., Ni, M., Ma, J., Zeng, F., Sun, S., Fu, J., et al. (2022) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2022.02.003 · Cited by 106 · see citing works
Afonso, M. B., Rodrigues, P. M., Mateus‐Pinheiro, M., Simão, A. L., Gaspar, M. M., Majdi, A., Arretxe, E., Alonso, C., Santos‐Laso, Á., Jiménez-Agüero, R., et al. (2020) · Gut · doi:10.1136/gutjnl-2020-321767 · Cited by 103 · see citing works
Valenzuela, R., & Videla, L. A. (2020) · Nutrients · doi:10.3390/nu12020499 · Cited by 94 · see citing works
“Mice subjected to HFDs comprising 60% of the total calories as saturated fat, mainly from lard, for 12 weeks is considered as a suitable experimental approach for liver steatosis development, similar to that found in NAFLD patients [31].”
Suárez, M., Boqué, N., Bas-Prior, J. M. D., Mayneris‐Perxachs, J., Arola, L., & Caimari, A. (2017) · Nutrients · doi:10.3390/nu9101052 · Cited by 93 · see citing works
“In fact, animal models of NAFLD are commonly induced by choline and methionine-deficient diets [137].”
BackgroundJensen, V. S., Hvid, H., Damgaard, J., Nygaard, H., Ingvorsen, C., Wulff, E. M., Lykkesfeldt, J., & Fledelius, C. (2018) · Diabetology & Metabolic Syndrome · doi:10.1186/s13098-018-0307-8 · Cited by 92 · see citing works
“The realization that diet is an important contributor to the pathogenesis of NAFLD has resulted in a considerable variety of dietinduced animal models, where the majority (apart from those based on nutritional deficiencies) is based on a high-fat diet with varying levels of simple carbohydrate and cholesterol [17, 18].”
BackgroundTarantino, G., Balsano, C., Santini, S. J., Brienza, G., Clemente, I., Cosimini, B., & Sinatti, G. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222413424 · Cited by 90 · see citing works
Echeverría, F., Valenzuela, R., Bustamante, A., Álvarez, D., Ortíz, M., Espinosa, A., Illesca, P., Gonzalez‐Mañán, D., & Videla, L. A. (2019) · Food & Function · doi:10.1039/c9fo01373c · Cited by 86 · see citing works
Zhang, X., Lau, H. C.-H., & Yu, J. Q. (2025) · Pharmacological Reviews · doi:10.1016/j.pharmr.2024.100018 · Cited by 94 · see citing works
Self-citationEl‐Kashef, D. H., & Serrya, M. S. (2019) · Life Sciences · doi:10.1016/j.lfs.2019.05.019 · Cited by 84 · see citing works
Human Liver Spheroids as a Model to Study Aetiology and Treatment of Hepatic Fibrosis
Hurrell, T., Kastrinou‐Lampou, V., Fardellas, A., Hendriks, D. F. G., Nordling, Å., Johansson, I., Baze, A., Parmentier, C., Richert, L., & Ingelman‐Sundberg, M. (2020) · Cells · doi:10.3390/cells9040964 · Cited by 81 · see citing works
“While there are murine models for each stage of NAFLD, translational limitations and discrepancies in their histopathology and/or physiological properties cannot be overlooked [10].”
BackgroundElbadawy, M., Yamanaka, M., Goto, Y., Hayashi, K., Tsunedomi, R., Hazama, S., Nagano, H., Yoshida, T., Shibutani, M., Ichikawa, R., et al. (2020) · Biomaterials · doi:10.1016/j.biomaterials.2020.119823 · Cited by 79 · see citing works
Pathogenesis of Nonalcoholic Steatohepatitis and Hormone-Based Therapeutic Approaches
Kim, K. H., & Lee, M. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00485 · Cited by 77 · see citing works
“Numerous preclinical animal models based on genetic or dietary manipulation with relevance to human NAFLD/NASH have been developed to explore the mechanisms underlying the development of NAFLD/NASH and identify novel targets for its treatment (145, 146).”
BackgroundLi, D., Cui, Y., Wang, X., Liu, F., & Li, X. (2021) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.1c02532 · Cited by 72 · see citing works
Zeng, H., Larson, K., Cheng, W., Bukowski, M. R., Safratowich, B. D., Liu, Z., & Hakkak, R. (2020) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2019.108336 · Cited by 74 · see citing works
Belenguer, G., Mastrogiovanni, G., Pacini, C., Hall, Z., Dowbaj, A. M., Arnes-Benito, R., Sljukic, A., Prior, N., Kakava, S., Bradshaw, C. R., et al. (2022) · Nature Communications · doi:10.1038/s41467-021-27923-z · Cited by 71 · see citing works
Chen, K., Ma, J., Jia, X., Ai, W., Ma, Z., & Pan, Q. (2018) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2018.11.005 · Cited by 70 · see citing works
NAFLD Preclinical Models: More than a Handful, Less of a Concern?
Oligschlaeger, Y., & Shiri‐Sverdlov, R. (2020) · Biomedicines · doi:10.3390/biomedicines8020028 · Cited by 65 · see citing works
Animal models of NAFLD from the pathologist's point of view
Denk, H., Abuja, P. M., & Zatloukal, K. (2018) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2018.04.024 · Cited by 64 · see citing works
Teng, Y., Zhao, Z., Tasnim, F., Huang, X., & Yu, H. (2021) · Biomaterials · doi:10.1016/j.biomaterials.2021.120904 · Cited by 62 · see citing works
Echeverría, F., Valenzuela, R., Bustamante, A., Álvarez, D., Ortíz, M., Soto-Alarcón, S. A., Muñoz, P., Corbari, A., & Videla, L. A. (2018) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2018/5109503 · Cited by 63 · see citing works
Cho, H., Kim, H., Lee, K., Lasli, S., Ung, A., Hoffman, T., Nasiri, R., Bandaru, P., Ahadian, S., Dokmeci, M. R., et al. (2021) · Small · doi:10.1002/smll.202007425 · Cited by 62 · see citing works
“Taken together, the proposed platform will enable a better understanding of the mechanisms underlying fibrosis progression in NAFLD as well as the identification of new drugs for the different stages of NAFLD.”
BackgroundInfluentialYang, Y., Wu, Y., Zou, J., Wang, Y., Xu, M., Huang, W., Yu, D., Zhang, L. R., Zhang, Y., & Sun, X.-D. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.687095 · Cited by 62 · see citing works
“Rats of the HFD group and NAR groups were fed with an HFD (60% fat calories, HFK Bioscience, Beijing, China) for 12 weeks (Lau et al., 2017).”
MethodNguyen, H. T., Gu, M., Werlinger, P., Cho, J.-H., Cheng, J., & Suh, J. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232113436 · Cited by 64 · see citing works
Zheng, L., Yin, L., Xu, L., Qi, Y., Li, H., Xu, Y., Han, X., Liu, K., & Peng, J. (2017) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2017.10.153 · Cited by 62 · see citing works
Non-alcoholic fatty liver disease development: A multifactorial pathogenic phenomena
Bashir, A., Duseja, A. K., De, A., Mehta, M., & Tiwari, P. (2022) · Liver Research · doi:10.1016/j.livres.2022.05.002 · Cited by 64 · see citing works
Chen, Y.-S., Wang, W., Morgan, M., Robson, T., & Annett, S. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1148934 · Cited by 63 · see citing works
The hepatokine Tsukushi is released in response to NAFLD and impacts cholesterol homeostasis
Mouchiroud, M., Camiré, É., Aldow, M., Caron, A., Jubinville, É., Turcotte, L., Kaci, I., Beaulieu, M.-J., Roy, C., Labbé, S. M., et al. (2019) · JCI Insight · doi:10.1172/jci.insight.129492 · Cited by 57 · see citing works
An update on animal models of liver fibrosis
Wu, S., Wang, X., Xing, W., Li, F., Liang, M., Li, K., He, Y., & Wang, J. (2023) · Frontiers in Medicine · doi:10.3389/fmed.2023.1160053 · Cited by 71 · see citing works
Ginsenoside Rg1 Regulates Liver Lipid Factor Metabolism in NAFLD Model Rats
Hou, Y., Gu, D., Peng, J., Jiang, K., Li, Z., Shi, J., Yang, S., Li, S.-D., & Fan, X. (2020) · ACS Omega · doi:10.1021/acsomega.0c00529 · Cited by 57 · see citing works
Shi, T., Wu, L., Ma, W., Ju, L., Bai, M., Chen, X., Liu, S., Yang, X., & Shi, J. (2020) · Evidence-based Complementary and Alternative Medicine · doi:10.1155/2020/8749564 · Cited by 55 · see citing works
Faitot, F., Besch, C., Battini, S., Ruhland, E., Onea, M. A., Addeo, P., Woehl‐Jaegle, M., Ellero, B., Bachellier, P., & Namer, I. J. (2017) · Journal of Hepatology · doi:10.1016/j.jhep.2017.11.022 · Cited by 54 · see citing works
Sales, R. C., Medeiros, P. D. C., Fernandes, F. S., de Velasco, P. C., Gonçalves, F., Martín‐Hernández, R., Mantilla-Escalante, D. C., Gil‐Zamorano, J., Peres, W. A. F., de Souza, S. A. L., et al. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms20010008 · Cited by 52 · see citing works
“More recently, high-fat diets have been used to induce NAFLD in animals, in order to study both the pathophysiology and possible treatments for this disease [27,28].”
BackgroundMethodLi, X., Wang, Z., & Klaunig, J. E. (2018) · Toxicology · doi:10.1016/j.tox.2018.08.007 · Cited by 52 · see citing works
Rothbauer, M., Bachmann, B., Eilenberger, C., Kratz, S. R. A., Spitz, S., Höll, G., & Ertl, P. (2021) · Micromachines · doi:10.3390/mi12050470 · Cited by 51 · see citing works
MicroRNA-29a Disrupts DNMT3b to Ameliorate Diet-Induced Non-Alcoholic Steatohepatitis in Mice
Yang, Y., Kuo, H., Wang, F., & Huang, Y. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20061499 · Cited by 51 · see citing works
“The animal model of MCD diet better mimicked the pathological findings of human NASH than did other dietary models [32].”
BackgroundOh, S., Son, M., Byun, K.-A., Jang, J. T., Choi, C. H., Son, K. H., & Byun, K. (2021) · Marine Drugs · doi:10.3390/md19060318 · Cited by 51 · see citing works
Li, S., Wang, N., Hong, M., Tan, H., Pan, G., & Feng, Y. (2018) · Molecules · doi:10.3390/molecules23020352 · Cited by 50 · see citing works
“Both ALD and NAFLD may progress from simple steatosis to hepatitis, fibrosis and cirrhosis [4].”
BackgroundWang, D., Lao, L., Pang, X., Qiao, Q., Pang, L., Feng, Z., Bai, F., Sun, X., Lin, X., & Wei, J. (2018) · International Immunopharmacology · doi:10.1016/j.intimp.2018.10.013 · Cited by 50 · see citing works
Zhu, W., Zhang, M., Chang, L., Zhu, W., Li, C., Xie, F., Zhang, H., Zhao, T., & Jiang, J. (2019) · Frontiers in Zoology · doi:10.1186/s12983-019-0341-x · Cited by 50 · see citing works
Simões, I. C. M., Karkucińska‐Więckowska, A., Janikiewicz, J., Szymańska, S., Pronicki, M., Dobrzyń, P., Dąbrowski, M., Dobrzyń, A., Oliveira, P. J., Zischka, H., et al. (2020) · Antioxidants · doi:10.3390/antiox9100995 · Cited by 50 · see citing works
Dua, A., KUMARI, R. R., Singh, M., Kumar, R., Pradeep, S., Ojesina, A. I., & Kumar, R. (2025) · Frontiers in Medicine · doi:10.3389/fmed.2025.1618275 · Cited by 53 · see citing works
“While existing models continue to guide mechanistic research and therapeutic testing, further development of models that more closely align with human pathophysiology is crucial to improve translational validity (295, 303, 304).”
Hassan, N. F., Nada, S. A., Hassan, A. M., El‐Ansary, M. R., Al‐Shorbagy, M. Y., & Abdelsalam, R. M. (2019) · Inflammation · doi:10.1007/s10753-019-00967-6 · Cited by 46 · see citing works
Lad, A. C., Su, R. C., Breidenbach, J. D., Stemmer, P. M., Carruthers, N. J., Sanchez, N. M., Khalaf, F. K., Zhang, S., Kleinhenz, A. L., Dube, P. R., et al. (2019) · Toxins · doi:10.3390/toxins11090486 · Cited by 47 · see citing works
“In the current study, we used Leprdb/J mice, a well-established genetic model for NAFLD [42], to examine the effect of prolonged low dose oral exposure to MC-LR in mice with pre-existing liver disease.”
MethodGurevich, I., Burton, S., Munn, C. G., Ohshima, M., Goedland, M., Czysz, K., & Rajesh, D. (2020) · Biology Open · doi:10.1242/bio.055087 · Cited by 47 · see citing works
Khairnar, R., Islam, M. A., Fleishman, J. S., & Kumar, S. (2022) · Life Sciences · doi:10.1016/j.lfs.2022.121185 · Cited by 46 · see citing works
Highly Sensitive Two-Photon Lipid Droplet Tracker for In Vivo Screening of Drug Induced Liver Injury
Lee, H. W., Lee, I.-J., Lee, S., Kim, Y. R., & Kim, H. M. (2022) · ACS Sensors · doi:10.1021/acssensors.1c02679 · Cited by 46 · see citing works
Mouse models of non‐alcoholic steatohepatitis: A reflection on recent literature
Haczeyni, F., Yeh, M. M., Ioannou, G. N., Leclercq, I. A., Goldin, R. D., Dan, Y. Y., Yu, J. Q., Teoh, N., & Farrell, G. C. (2018) · Journal of Gastroenterology and Hepatology · doi:10.1111/jgh.14122 · Cited by 44 · see citing works
Self-citationObeticholic acid and INT-767 modulate collagen deposition in a NASH in vitro model
Anfuso, B., Tiribelli, C., Adorini, L., & Rosso, N. (2020) · Scientific Reports · doi:10.1038/s41598-020-58562-x · Cited by 43 · see citing works
Signaling Nodes Associated with Endoplasmic Reticulum Stress during NAFLD Progression
Koo, J. H., & Han, C. Y. (2021) · Biomolecules · doi:10.3390/biom11020242 · Cited by 42 · see citing works
“However, these models only partially reflect the stepwise progressive pattern of human NAFLD, in that early metabolic dysregulation observed in the disease is not accompanied in the experimental models even when fibrotic lesions begin to appear [41,42].”
BackgroundGabbia, D., Roverso, M., Guido, M., Sacchi, D., Scaffidi, M., Carrara, M., Orso, G., Russo, F. P., Floreani, A., Bogialli, S., et al. (2019) · Nutrients · doi:10.3390/nu11071602 · Cited by 42 · see citing works
“, [40] and refs therein) leads to the development of NAFLD, a liver disease associated with a Western diet and lifestyle.”
BackgroundSex differences in diet-induced MASLD – are female mice naturally protected?
Meyer, J., Teixeira, A. M., Richter, S., Larner, D. P., Syed, A., Klöting, N., Matz‐Soja, M., Gaul, S., Barnikol-Oettler, A., Kiess, W., et al. (2025) · Frontiers in Endocrinology · doi:10.3389/fendo.2025.1567573 · Cited by 41 · see citing works
“As expected, both male and female mice on FFD gained more weight over the course of the study than mice on CD, with a bigger increase in male compared to female mice on FFD, as has previously been shown in other studies (14, 22, 38).”
Ahmed, L. A., Salem, M. B., el-Din, S. H. S., El-Lakkany, N. M., Okasha, H., Nasr, S. M., Hammam, O. A., Botros, S. S., & Saleh, S. (2020) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2020.173461 · Cited by 40 · see citing works
Gentiopicroside improves NASH and liver fibrosis by suppressing TLR4 and NLRP3 signaling pathways
Yong, Q., Huang, C., Chen, B., An, J., Zheng, Y., Zhao, L., Peng, C., & Liu, F. (2024) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2024.116952 · Cited by 40 · see citing works
Heinrich, G., Ghadieh, H. E., Ghanem, S. S., Muturi, H. T., Rezaei, K., Al–Share, Q. Y., Bowman, T. A., Zhang, D., Garofalo, R. S., Yin, L., et al. (2017) · Frontiers in Endocrinology · doi:10.3389/fendo.2017.00008 · Cited by 42 · see citing works
Radhakrishnan, S., Ke, J., & Pellizzon, M. (2020) · Current Developments in Nutrition · doi:10.1093/cdn/nzaa078 · Cited by 40 · see citing works
“These types of models have been extensively reviewed elsewhere (2, 4, 23, 112, 114).”
BackgroundLi, S., Zhang, Y., Liu, N., Chen, J., Guo, L., Dai, Z., Wang, C., Wu, Z., & Wu, G. (2020) · Journal of Animal Science and Biotechnology/Journal of animal science and biotechnology · doi:10.1186/s40104-020-00486-7 · Cited by 40 · see citing works
Experimental models of metabolic and alcoholic fatty liver disease
Buyco, D. G., Martin, J., Jeon, S., Hooks, R., Lin, C., & Carr, R. M. (2020) · World Journal of Gastroenterology · doi:10.3748/wjg.v27.i1.1 · Cited by 40 · see citing works
Longo, L., Ferrari, J. T., Rampelotto, P. H., Dellavia, G. H., Pasqualotto, A., de Oliveira, C. P. M. S., Cerski, C. T. S., da Silveira, T. R., Cruz, C. U., & Álvares‐da‐Silva, M. R. (2020) · Clinical and Experimental Gastroenterology · doi:10.2147/ceg.s262879 · Cited by 39 · see citing works
Germ‐free mice are not protected against diet‐induced obesity and metabolic dysfunction
Moretti, C. H., Schiffer, T. A., Li, X., Weitzberg, E., Carlström, M., & Lundberg, J. O. (2020) · Acta Physiologica · doi:10.1111/apha.13581 · Cited by 38 · see citing works
SMN Depleted Mice Offer a Robust and Rapid Onset Model of Nonalcoholic Fatty Liver Disease
Deguise, M., Pileggi, C. A., Repentigny, Y. D., Beauvais, A., Tierney, A., Chehadé, L., Michaud, J., Hurtado, M. L., Lamont, D. J., Atrih, A., et al. (2021) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2021.01.019 · Cited by 38 · see citing works
“The ob/ob and db/db mutant mice, which display altered leptin signaling, have metabolic features but no inflammation or fibrosis.(6,10,11) The high-fat diet appears to result in all features of the NAFLD spectrum; however, fibrosis is minimal and can take up to 36–50 weeks to develop.”
BackgroundMethodCarlessi, R., Köhn‐Gaone, J., Olynyk, J. K., & Tirnitz‐Parker, J. E. E. (2019) · Codon Publications eBooks · doi:10.15586/hepatocellularcarcinoma.2019 · Cited by 37 · see citing works
Luo, N., Yang, C., Zhu, Y., Chen, Q., & Zhang, B. (2021) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.0c06652 · Cited by 37 · see citing works
Application of Disulfiram and its Metabolites in Treatment of Inflammatory Disorders
Guo, W., Chen, S., Li, C., Xu, J., & Wang, L. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.795078 · Cited by 37 · see citing works
“NASH manifests itself as steatosis and inflammatory damage to the hepatocyte.”
BackgroundInfluentialKjærgaard, K., Mikkelsen, A. C. D., Landau, A. M., Eriksen, P. L., Hamilton-Dutoit, S. J., Magnusson, N. E., Thomsen, M. B., Chen, F., Vilstrup, H., Mookerjee, R. P., et al. (2023) · JHEP Reports · doi:10.1016/j.jhepr.2023.100992 · Cited by 38 · see citing works
“51 However, our model does emphasise the direct effect of MASLD, since animals had severe steatosis and in fl ammation associated with cognitive disturbances that could not be attributed to brain insulin resistance or cardiovascular complications.”
BackgroundPathogenesis of and major animal models used for nonalcoholic fatty liver disease
Jiang, M., Wu, N., Chen, X., Wang, W., Chu, Y., Liu, H., Li, W., Chen, D., Li, X., & Xu, B. (2019) · Journal of International Medical Research · doi:10.1177/0300060519833527 · Cited by 36 · see citing works
“However, congenital leptin deficiency or leptin resistance caused by gene mutations is not prevalent in obese humans or NASH patients, so the ob/ob and db/db mice models are limited in their ability to reflect the genesis of human obesity or NASH.(63,78)”
BackgroundLiver Protective Effect of Fenofibrate in NASH/NAFLD Animal Models
Mahmoudi, A. A., Moallem, S. A., Johnston, T. P., & Sahebkar, A. (2022) · PPAR Research · doi:10.1155/2022/5805398 · Cited by 36 · see citing works
A new method to induce nonalcoholic steatohepatitis (NASH) in mice
Savari, F., Mard, S. A., Badavi, M., Rezaie, A., & Gharib-Naseri, M. K. (2019) · BMC Gastroenterology · doi:10.1186/s12876-019-1041-x · Cited by 35 · see citing works
Skubic, C., Drakulić, Ž., & Rozman, D. (2018) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1080/17425255.2018.1492552 · Cited by 34 · see citing works
“The pathology of different stages and causes of NAFLD are similar in mice and humans [41].”
BackgroundArman, T., Lynch, K. D., Montonye, M. L., Goedken, M. J., & Clarke, J. (2019) · Toxins · doi:10.3390/toxins11070398 · Cited by 34 · see citing works
Huang, X., Chen, Q., Fan, Y., Yang, R., Gong, G., Yan, C., Song, Y., Zhang, B., Xi, S., Huang, Y., et al. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.114300 · Cited by 33 · see citing works
Valenzuela, R., & Videla, L. A. (2017) · Pharmacological Research · doi:10.1016/j.phrs.2017.12.013 · Cited by 32 · see citing works
“The HFD model is extensively used in experimental protocols related to NAFLD, considering that this diet has 60% of its energy as fat (principally saturated fat) and that is not deficient in macro (proteins and amino acids) and micronutrients (vitamins) [32,33].”
MethodImmunoregulatory Effect of Koumine on Nonalcoholic Fatty Liver Disease Rats
Yue, R., Jin, G., Wei, S., Huang, H., Su, L., Zhang, C., Xu, Y., Yang, J., Liu, M., Chu, Z.-Y., et al. (2019) · Journal of Immunology Research · doi:10.1155/2019/8325102 · Cited by 32 · see citing works
Schumacher-Petersen, C., Christoffersen, B. Ø., Kirk, R. K., Ludvigsen, T. P., Zois, N. E., Pedersen, H. D., Vyberg, M., & Olsen, L. H. (2019) · Journal of Translational Medicine · doi:10.1186/s12967-019-1854-y · Cited by 32 · see citing works
- Authors
- Lau, J. K. C., Zhang, X., & Yu, J.
- Affiliations
- Chinese University of Hong Kong (HK)
- Corresponding author
- Yu, Jun
- ORCID
- Venue
- The Journal of Pathology
- Publisher
- Wiley
- Published
- 2016-11-22
- Volume
- 241
- Issue
- 1
- Pages
- 36-44
- ISSN
- 0022-3417 (ISSN-L)
- 1096-9896
- PMC
- PMC5215469
- OpenAlex
- W2532614692
- Cited by
- 373
- References
- 71
- Citations by year
- 2026: 28 · 2025: 32 · 2024: 38 · 2023: 31 · 2022: 37 · 2021: 42 · 2020: 56 · 2019: 59 · 2018: 36 · 2017: 14
- FWCI
- 4.92
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The Journal of Pathology (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- RGC-GRF Hong Kong (1406415)
- National Basic Research Programme of China (2013CB531401)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
- Keywords
- non-alcoholic fatty liver disease, animal models, hepatic steatosis, nonalcoholic steatohepatitis, liver fibrosis, hepatocellular carcinoma, NAFLD pathogenesis, therapeutic target
- MeSH terms
- Animals, Diet, Disease Models, Animal, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Cytokines, Oxidative Stress, Disease Progression, Genetic Predisposition to Disease, 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
