{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T04:36:18Z","timestamp":1790829378872,"version":"4.1.0"},"reference-count":33,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,2,20]],"date-time":"2025-02-20T00:00:00Z","timestamp":1740009600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Two different diets able to induce dietary hyperammonaemia (a methionine\u2013choline-deficient (MCD) diet and a methionine-deficient diet enriched with ammonium acetate (MAD + 20% ammonium acetate)) were tested in a rat model. The diets were shown to have different modes of action, inducing significant hyperammonaemia (HA) and growth retardation in the rats, with different metabolic consequences. The MCD diet resulted in the development of endogenous HA, with a decrease in bilirubin levels and an increase in hepatic fat content. In contrast, the MAD + 20% ammonium acetate diet increased circulating ALP and haptoglobin levels and decreased liver mass. The above results suggest that the MCD diet deteriorated the liver function of the rats, resulting in the development of endogenous HA, while the MAD diet caused moderate changes in liver metabolism, resulting in the development of exogenous HA. Interestingly, the commonly used oral treatments Lactulose and Rifaximin did not ameliorate hyperammonaemia during or after the treatment period. In conclusion, even though the diets used in the current study caused somewhat similar hyperammonaemia, they seemed to provoke different metabolic consequences. The latter can have an impact on the severity of the resulting hyperammonaemia and thus on the hyperammonaemia-induced encephalopathy, resulting in the development of distinguishing cognitive and metabolic (liver) effects compared to other forms of encephalopathy. We hypothesized that these rat models, with significantly increased serum ammonia levels, along with different liver injuries, could serve as a suitable double animal model for the testing of new, oral enzyme therapies for hepatic encephalopathy in future studies.<\/jats:p>","DOI":"10.3390\/ijms26051818","type":"journal-article","created":{"date-parts":[[2025,2,20]],"date-time":"2025-02-20T11:03:37Z","timestamp":1740049417000},"page":"1818","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Rat Model of Endogenous and Exogenous Hyperammonaemia Induced by Different Diets"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5072-016X","authenticated-orcid":false,"given":"Janine","family":"Donaldson","sequence":"first","affiliation":[{"name":"School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Parktown, Johannesburg 2193, South Africa"},{"name":"Anara AB, 23132 Trelleborg, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomasz","family":"Jacek","sequence":"additional","affiliation":[{"name":"National Research Institute of Animal Production, 32-083 Balice, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6286-5697","authenticated-orcid":false,"given":"Piotr","family":"Wychowa\u0144ski","sequence":"additional","affiliation":[{"name":"Department of Head and Neck and Sensory Organs, Division of Oral Surgery and Implantology, Institute of Clinical Dentistry, Gemelli Foundation for the University Policlinic, Catholic University of the \u201cSacred Heart\u201d, 00168 Rome, Italy"},{"name":"Department of Interventional Dentistry, Collegium Medicum, Nicolaus Copernicus University, 85-067 Bydgoszcz, Poland"},{"name":"Specialized Private Implantology Clinic Wychowa\u0144ski Stomatologia, 02-517 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4538-3159","authenticated-orcid":false,"given":"Kamil","family":"Zaworski","sequence":"additional","affiliation":[{"name":"Department of Animal Physiology, The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, 05-110 Jab\u0142onna, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5898-3909","authenticated-orcid":false,"given":"Dominika","family":"Szkopek","sequence":"additional","affiliation":[{"name":"Large Animal Models Laboratory, The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, 05-110 Jab\u0142onna, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8645-1045","authenticated-orcid":false,"given":"Jaros\u0142aw","family":"Woli\u0144ski","sequence":"additional","affiliation":[{"name":"Large Animal Models Laboratory, The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, 05-110 Jab\u0142onna, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danica","family":"Grujic","sequence":"additional","affiliation":[{"name":"Anara AB, 23132 Trelleborg, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0308-3214","authenticated-orcid":false,"given":"Stefan","family":"Pierzynowski","sequence":"additional","affiliation":[{"name":"Anara AB, 23132 Trelleborg, Sweden"},{"name":"Department of Biology, Lund University, 223 62 Lund, Sweden"},{"name":"Department of Medical Biology, Institute of Rural Health, 20-090 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3290-339X","authenticated-orcid":false,"given":"Kateryna","family":"Pierzynowska","sequence":"additional","affiliation":[{"name":"Anara AB, 23132 Trelleborg, Sweden"},{"name":"Department of Animal Physiology, The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, 05-110 Jab\u0142onna, Poland"},{"name":"Department of Biology, Lund University, 223 62 Lund, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2073","DOI":"10.1007\/s11011-017-0098-x","article-title":"Lactulose Decreases Neuronal Activation and Attenuates Motor Behavioral Deficits in Hyperammonemic Rats","volume":"32","author":"Mendes","year":"2017","journal-title":"Metab. Brain Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1474","DOI":"10.1111\/liv.14911","article-title":"2021 ISHEN Guidelines on Animal Models of Hepatic Encephalopathy","volume":"41","author":"DeMorrow","year":"2021","journal-title":"Liver Int."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"173","DOI":"10.4254\/wjh.v11.i2.173","article-title":"Hepatic Encephalopathy: Lessons from Preclinical Studies","volume":"11","author":"Lima","year":"2019","journal-title":"World J. Hepatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1002\/hep.1840100310","article-title":"A Simple Animal Model of Hyperammonemia","volume":"10","author":"Felipo","year":"1989","journal-title":"Hepatology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1016\/j.jhep.2020.04.011","article-title":"Animal Models for Liver Disease\u2014A Practical Approach for Translational Research","volume":"73","author":"Nevzorova","year":"2020","journal-title":"J. Hepatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"14","DOI":"10.21037\/jlpm-23-64","article-title":"Investigative Algorithms for Disorders Affecting Plasma Transaminases (Aspartate Transaminase and Alanine Transaminase)\u2014A Narrative Review","volume":"9","author":"Shipman","year":"2024","journal-title":"J. Lab. Precis. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"200","DOI":"10.2478\/enr-2023-0024","article-title":"Role of Liver Parameters in Diabetes Mellitus\u2014A Narrative Review","volume":"57","author":"Rafaqat","year":"2023","journal-title":"Endocr. Regul."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1503\/cmaj.1040752","article-title":"Liver Enzyme Alteration: A Guide for Clinicians","volume":"172","author":"Giannini","year":"2005","journal-title":"Can. Med. Assoc. J."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1155\/2008\/589394","article-title":"Effect of Withania Somnifera Root Powder on the Levels of Circulatory Lipid Peroxidation and Liver Marker Enzymes in Chronic Hyperammonemia","volume":"5","author":"Harikrishnan","year":"2008","journal-title":"J. Chem."},{"key":"ref_10","first-page":"1648","article-title":"The Effects of Allopurinol on Rat Liver and Spleen Tissues in a Chronic Hyperammonemia Animal Model","volume":"28","author":"Gokcimen","year":"2007","journal-title":"Saudi Med. J."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1097\/MOG.0b013e32834e7b4b","article-title":"Choline Metabolism Provides Novel Insights into Nonalcoholic Fatty Liver Disease and Its Progression","volume":"28","author":"Corbin","year":"2012","journal-title":"Curr. Opin. Gastroenterol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1177\/0023677215570078","article-title":"Mouse Models of Metabolic Liver Injury","volume":"49","author":"Ramadori","year":"2015","journal-title":"Lab. Anim."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Nababan, S.H.H., Khairunissa, S.T., Erfan, E., Nafrialdi, N., Krisnuhoni, E., Hasan, I., and Gani, R.A. (2021). Choline-Deficient High-Fat Diet-Induced Steatohepatitis in BALB\/c Mice. Mol. Cell. Biomed. Sci., 5.","DOI":"10.21705\/mcbs.v5i2.193"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Osipova, D., Kokoreva, K., Lazebnik, L., Golovanova, E., Pavlov, C., Dukhanin, A., Orlova, S., and Starostin, K. (2022). Regression of Liver Steatosis Following Phosphatidylcholine Administration: A Review of Molecular and Metabolic Pathways Involved. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.797923"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1016\/j.jhep.2018.06.023","article-title":"Urea Cycle Dysregulation in Non-Alcoholic Fatty Liver Disease","volume":"69","author":"Marrone","year":"2018","journal-title":"J. Hepatol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Vallianou, N., Christodoulatos, G.S., Karampela, I., Tsilingiris, D., Magkos, F., Stratigou, T., Kounatidis, D., and Dalamaga, M. (2021). Understanding the Role of the Gut Microbiome and Microbial Metabolites in Non-Alcoholic Fatty Liver Disease: Current Evidence and Perspectives. Biomolecules, 12.","DOI":"10.3390\/biom12010056"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"G295","DOI":"10.1152\/ajpgi.00036.2014","article-title":"Experimental Nonalcoholic Steatohepatitis Compromises Ureagenesis, an Essential Hepatic Metabolic Function","volume":"307","author":"Thomsen","year":"2014","journal-title":"Am. J. Physiol.-Gastrointest. Liver Physiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"155952","DOI":"10.1016\/j.metabol.2024.155952","article-title":"The Lipopolysaccharide-TLR4 Axis Regulates Hepatic Glutaminase 1 Expression Promoting Liver Ammonia Build-up as Steatotic Liver Disease Progresses to Steatohepatitis","volume":"158","author":"Kerbert","year":"2024","journal-title":"Metabolism"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"E191","DOI":"10.1152\/ajpendo.00405.2020","article-title":"Bilirubin as a Metabolic Hormone: The Physiological Relevance of Low Levels","volume":"320","author":"Creeden","year":"2021","journal-title":"Am. J. Physiol.-Endocrinol. Metab."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"383","DOI":"10.3350\/cmh.2012.18.4.383","article-title":"Serum Bilirubin Levels Are Inversely Associated with Nonalcoholic Fatty Liver Disease","volume":"18","author":"Kwak","year":"2012","journal-title":"Clin. Mol. Hepatol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Tian, J., Zhong, R., Liu, C., Tang, Y., Gong, J., Chang, J., Lou, J., Ke, J., Li, J., and Zhang, Y. (2016). Association between Bilirubin and Risk of Non-Alcoholic Fatty Liver Disease Based on a Prospective Cohort Study. Sci. Rep., 6.","DOI":"10.1038\/srep31006"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"522","DOI":"10.21037\/atm-22-1187","article-title":"Association between Bilirubin and Nonalcoholic Fatty Liver Disease in the Non-Obese Chinese Population: A Cross-Sectional Study","volume":"10","author":"Shu","year":"2022","journal-title":"Ann. Transl. Med."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Bellarosa, C., Bedogni, G., Bianco, A., Cicolini, S., Caroli, D., Tiribelli, C., and Sartorio, A. (2021). Association of Serum Bilirubin Level with Metabolic Syndrome and Non-Alcoholic Fatty Liver Disease: A Cross-Sectional Study of 1672 Obese Children. J. Clin. Med., 10.","DOI":"10.3390\/jcm10132812"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1002\/ajh.23623","article-title":"Haptoglobin Testing in Hemolysis: Measurement and Interpretation","volume":"89","author":"Shih","year":"2014","journal-title":"Am. J. Hematol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1007\/s13105-012-0186-7","article-title":"Haptoglobin and the Inflammatory and Oxidative Status in Experimental Diabetic Rats: Antioxidant Role of Haptoglobin","volume":"69","author":"Jelena","year":"2013","journal-title":"J. Physiol. Biochem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1002\/jnr.23159","article-title":"Elevated Serum Haptoglobin after Traumatic Brain Injury Is Synthesized Mainly in Liver","volume":"91","author":"Yang","year":"2013","journal-title":"J. Neurosci. Res."},{"key":"ref_27","first-page":"647","article-title":"Biological Functions of Haptoglobin--New Pieces to an Old Puzzle","volume":"35","author":"Dobryszycka","year":"1997","journal-title":"Eur. J. Clin. Chem. Clin. Biochem."},{"key":"ref_28","first-page":"e28016","article-title":"Hepatic Encephalopathy and Treatment Modalities: A Review Article","volume":"14","author":"Sharma","year":"2022","journal-title":"Cureus"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"908","DOI":"10.3748\/wjg.v11.i6.908","article-title":"Comparison of Probiotics and Lactulose in the Treatment of Minimal Hepatic Encephalopathy in Rats","volume":"11","author":"Jia","year":"2005","journal-title":"World J. Gastroenterol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2084","DOI":"10.3748\/wjg.v18.i17.2084","article-title":"Rifaximin, but Not Growth Factor 1, Reduces Brain Edema in Cirrhotic Rats","volume":"18","year":"2012","journal-title":"World J. Gastroenterol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.ejphar.2016.03.024","article-title":"Development of an Experimental Rat Model of Hyperammonemic Encephalopathy and Evaluation of the Effects of Rifaximin","volume":"779","author":"Tamaoki","year":"2016","journal-title":"Eur. J. Pharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Mopuri, R., Kalyesubula, M., Rosov, A., Edery, N., Moallem, U., and Dvir, H. (2021). Improved Folch Method for Liver-Fat Quantification. Front. Vet. Sci., 7.","DOI":"10.3389\/fvets.2020.594853"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/S0021-9258(18)64849-5","article-title":"A Simple Method for the Isolation and Purification of Total Lipides from Animal Tissues","volume":"226","author":"Folch","year":"1957","journal-title":"J. Biol. Chem."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/5\/1818\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:38:52Z","timestamp":1760027932000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/5\/1818"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,20]]},"references-count":33,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2025,3]]}},"alternative-id":["ijms26051818"],"URL":"https:\/\/doi.org\/10.3390\/ijms26051818","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,20]]}}}