{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T10:49:29Z","timestamp":1793270969328,"version":"4.5.0"},"reference-count":36,"publisher":"Elsevier BV","issue":"4","license":[{"start":{"date-parts":[[2018,10,1]],"date-time":"2018-10-01T00:00:00Z","timestamp":1538352000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2018,10,1]],"date-time":"2018-10-01T00:00:00Z","timestamp":1538352000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"}],"funder":[{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004836","name":"Danish Council for Independent Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004836","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004837","name":"Ministerio de Ciencia e Innovaci\u00f3n","doi-asserted-by":"publisher","award":["SAF2014-51851-R"],"award-info":[{"award-number":["SAF2014-51851-R"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004837","name":"Ministerio de Ciencia e Innovaci\u00f3n","doi-asserted-by":"publisher","award":["FIS PI15\/00035 ISCIII"],"award-info":[{"award-number":["FIS PI15\/00035 ISCIII"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["clinicalkey.com","clinicalkey.com.au","clinicalkey.es","clinicalkey.fr","clinicalkey.jp","journal-of-hepatology.eu","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Journal of Hepatology"],"published-print":{"date-parts":[[2018,10]]},"DOI":"10.1016\/j.jhep.2018.06.023","type":"journal-article","created":{"date-parts":[[2018,7,4]],"date-time":"2018-07-04T23:24:18Z","timestamp":1530746658000},"page":"905-915","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":196,"title":["Urea cycle dysregulation in non-alcoholic fatty liver disease"],"prefix":"10.1016","volume":"69","author":[{"given":"Francesco","family":"De Chiara","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Heeb\u00f8ll","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9029-7378","authenticated-orcid":false,"given":"Giusi","family":"Marrone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmina","family":"Montoliu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Hamilton-Dutoit","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Ferrandez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fausto","family":"Andreola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krista","family":"Rombouts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henning","family":"Gr\u00f8nb\u00e6k","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vicente","family":"Felipo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordi","family":"Gracia-Sancho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajeshwar P.","family":"Mookerjee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hendrik","family":"Vilstrup","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajiv","family":"Jalan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen Louise","family":"Thomsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.jhep.2018.06.023_b0005","doi-asserted-by":"crossref","first-page":"1537","DOI":"10.1016\/S0140-6736(13)62152-2","article-title":"Liver disease in the UK: a Lancet Commission","volume":"382","author":"Williams","year":"2013","journal-title":"Lancet"},{"key":"10.1016\/j.jhep.2018.06.023_b0010","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1016\/j.jhep.2012.12.005","article-title":"The burden of liver disease in Europe: a review of available epidemiological data","volume":"58","author":"Blachier","year":"2013","journal-title":"J Hepatol"},{"key":"10.1016\/j.jhep.2018.06.023_b0015","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1016\/S0016-5085(99)70506-8","article-title":"Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity","volume":"116","author":"Matteoni","year":"1999","journal-title":"Gastroenterology"},{"key":"10.1016\/j.jhep.2018.06.023_b0020","doi-asserted-by":"crossref","first-page":"e180","DOI":"10.1111\/liv.12523","article-title":"Are oxidative stress mechanisms the common denominator in the progression from hepatic steatosis towards non-alcoholic steatohepatitis (NASH)?","volume":"34","author":"Tariq","year":"2014","journal-title":"Liver Int"},{"key":"10.1016\/j.jhep.2018.06.023_b0025","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1002\/hep.27368","article-title":"Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up","volume":"61","author":"Ekstedt","year":"2015","journal-title":"Hepatology"},{"key":"10.1016\/j.jhep.2018.06.023_b0030","doi-asserted-by":"crossref","first-page":"e310","DOI":"10.1053\/j.gastro.2015.04.043","article-title":"Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease","volume":"149","author":"Angulo","year":"2015","journal-title":"Gastroenterology"},{"key":"10.1016\/j.jhep.2018.06.023_b0035","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1159\/000282094","article-title":"Molecular mechanisms of hepatic fibrosis in non-alcoholic steatohepatitis","volume":"28","author":"Rombouts","year":"2010","journal-title":"Dig Dis"},{"key":"10.1016\/j.jhep.2018.06.023_b0040","doi-asserted-by":"crossref","first-page":"2083","DOI":"10.1093\/ajcn\/30.12.2083","article-title":"Urea biosynthesis I. The urea cycle and relationships to the citric acid cycle","volume":"30","author":"Shambaugh","year":"1977","journal-title":"Am J Clin Nutr"},{"key":"10.1016\/j.jhep.2018.06.023_b0045","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1016\/j.jhep.2005.03.004","article-title":"NASH: a mitochondrial disease","volume":"42","author":"Pessayre","year":"2005","journal-title":"J Hepatol"},{"key":"10.1016\/j.jhep.2018.06.023_b0050","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":"10.1016\/j.jhep.2018.06.023_b0055","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1016\/j.jhep.2015.11.019","article-title":"Ammonia produces pathological changes in human hepatic stellate cells and is a target for therapy of portal hypertension","volume":"64","author":"Jalan","year":"2016","journal-title":"J Hepatol"},{"key":"10.1016\/j.jhep.2018.06.023_b0060","doi-asserted-by":"crossref","first-page":"1751","DOI":"10.1002\/hep.25889","article-title":"Histopathological algorithm and scoring system for evaluation of liver lesions in morbidly obese patients","volume":"56","author":"Bedossa","year":"2012","journal-title":"Hepatology"},{"key":"10.1016\/j.jhep.2018.06.023_b0065","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1186\/1471-2105-13-134","article-title":"Primer-BLAST: a tool to design target-specific primers for polymerase chain reaction","volume":"13","author":"Ye","year":"2012","journal-title":"BMC Bioinf"},{"key":"10.1016\/j.jhep.2018.06.023_b0070","doi-asserted-by":"crossref","first-page":"6136","DOI":"10.1073\/pnas.84.17.6136","article-title":"Structure of the rat ornithine carbamoyltransferase gene, a large, X chromosome-linked gene with an atypical promoter","volume":"84","author":"Takiguchi","year":"1987","journal-title":"Proc Natl Acad Sci U S A"},{"key":"10.1016\/j.jhep.2018.06.023_b0075","first-page":"1180","article-title":"Promoter and 11-kilobase upstream enhancer elements responsible for hepatoma cell-specific expression of the rat ornithine transcarbamylase gene","volume":"10","author":"Murakami","year":"1990","journal-title":"Mol Cell Biol"},{"key":"10.1016\/j.jhep.2018.06.023_b0080","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1016\/S0021-9258(17)42261-7","article-title":"Determination of tissue specificity of the enhancer by combinatorial operation of tissue-enriched transcription factors. Both HNF-4 and C\/EBP beta are required for liver-specific activity of the ornithine transcarbamylase enhancer","volume":"269","author":"Nishiyori","year":"1994","journal-title":"J Biol Chem"},{"key":"10.1016\/j.jhep.2018.06.023_b0085","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1007\/s11011-011-9269-3","article-title":"Contribution of hyperammonemia and inflammatory factors to cognitive impairment in minimal hepatic encephalopathy","volume":"27","author":"Felipo","year":"2012","journal-title":"Metab Brain Dis"},{"key":"10.1016\/j.jhep.2018.06.023_b0090","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1002\/oby.20008","article-title":"Alterations in adipocytokines and cGMP homeostasis in morbid obesity patients reverse after bariatric surgery","volume":"21","author":"Felipo","year":"2013","journal-title":"Obesity (Silver Spring)"},{"key":"10.1016\/j.jhep.2018.06.023_b0095","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1002\/hep.20701","article-title":"Design and validation of a histological scoring system for nonalcoholic fatty liver disease","volume":"41","author":"Kleiner","year":"2005","journal-title":"Hepatology"},{"key":"10.1016\/j.jhep.2018.06.023_b0100","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1007\/BF00280883","article-title":"Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man","volume":"28","author":"Matthews","year":"1985","journal-title":"Diabetologia"},{"key":"10.1016\/j.jhep.2018.06.023_b0105","doi-asserted-by":"crossref","first-page":"e0173914","DOI":"10.1371\/journal.pone.0173914","article-title":"A morphological method for ammonia detection in liver","volume":"12","author":"Gutierrez-de-Juan","year":"2017","journal-title":"PLoS ONE"},{"key":"10.1016\/j.jhep.2018.06.023_b0110","doi-asserted-by":"crossref","first-page":"e96801","DOI":"10.1371\/journal.pone.0096801","article-title":"IHC profiler: an open source plugin for the quantitative evaluation and automated scoring of immunohistochemistry images of human tissue samples","volume":"9","author":"Varghese","year":"2014","journal-title":"PLoS ONE"},{"key":"10.1016\/j.jhep.2018.06.023_b0115","doi-asserted-by":"crossref","first-page":"1705","DOI":"10.1053\/gast.2002.36572","article-title":"AGA technical review on nonalcoholic fatty liver disease","volume":"123","author":"Sanyal","year":"2002","journal-title":"Gastroenterology"},{"key":"10.1016\/j.jhep.2018.06.023_b0120","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1038\/sj.ijo.0800571","article-title":"Liver abnormalities in severely obese subjects: effect of drastic weight loss after gastroplasty","volume":"22","author":"Luyckx","year":"1998","journal-title":"Int J Obes Relat Metab Disord"},{"key":"10.1016\/j.jhep.2018.06.023_b0125","doi-asserted-by":"crossref","first-page":"1356","DOI":"10.1136\/gutjnl-2012-302962","article-title":"Epigenetic modification of liver mitochondrial DNA is associated with histological severity of nonalcoholic fatty liver disease","volume":"62","author":"Pirola","year":"2013","journal-title":"Gut"},{"key":"10.1016\/j.jhep.2018.06.023_b0130","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1038\/nrm.2016.23","article-title":"Mitonuclear communication in homeostasis and stress","volume":"17","author":"Quiros","year":"2016","journal-title":"Nat Rev Mol Cell Biol"},{"key":"10.1016\/j.jhep.2018.06.023_b0135","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1007\/978-1-4614-3573-0_4","article-title":"Assembly factors of human mitochondrial respiratory chain complexes: physiology and pathophysiology","volume":"748","author":"Ghezzi","year":"2012","journal-title":"Adv Exp Med Biol"},{"key":"10.1016\/j.jhep.2018.06.023_b0140","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1016\/S0014-5793(96)01344-0","article-title":"Long-chain fatty acids suppress the induction of urea cycle enzyme genes by glucocorticoid action","volume":"399","author":"Tomomura","year":"1996","journal-title":"FEBS Lett"},{"key":"10.1016\/j.jhep.2018.06.023_b0145","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/j.cmet.2013.07.004","article-title":"DNA methylation analysis in nonalcoholic fatty liver disease suggests distinct disease-specific and remodeling signatures after bariatric surgery","volume":"18","author":"Ahrens","year":"2013","journal-title":"Cell Metab"},{"key":"10.1016\/j.jhep.2018.06.023_b0150","doi-asserted-by":"crossref","first-page":"1076","DOI":"10.1053\/j.gastro.2013.07.047","article-title":"Relationship between methylome and transcriptome in patients with nonalcoholic fatty liver disease","volume":"145","author":"Murphy","year":"2013","journal-title":"Gastroenterology"},{"key":"10.1016\/j.jhep.2018.06.023_b0155","doi-asserted-by":"crossref","first-page":"5161","DOI":"10.3390\/ijms16035161","article-title":"Potential epigenetic mechanism in non-alcoholic Fatty liver disease","volume":"16","author":"Sun","year":"2015","journal-title":"Int J Mol Sci"},{"key":"10.1016\/j.jhep.2018.06.023_b0160","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1016\/j.ymgme.2013.08.022","article-title":"Transcriptomic and epigenetic changes in early liver steatosis associated to obesity: effect of dietary methyl donor supplementation","volume":"110","author":"Cordero","year":"2013","journal-title":"Mol Genet Metab"},{"key":"10.1016\/j.jhep.2018.06.023_b0165","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/s13148-015-0056-6","article-title":"Differential DNA methylation of genes involved in fibrosis progression in non-alcoholic fatty liver disease and alcoholic liver disease","volume":"7","author":"Zeybel","year":"2015","journal-title":"Clin Epigenetics"},{"key":"10.1016\/j.jhep.2018.06.023_b0170","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1101\/gad.947102","article-title":"DNA methylation patterns and epigenetic memory","volume":"16","author":"Bird","year":"2002","journal-title":"Genes Dev"},{"key":"10.1016\/j.jhep.2018.06.023_b0175","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1002\/prca.200900119","article-title":"Non-alcoholic fatty liver disease proteomics","volume":"4","author":"Rodriguez-Suarez","year":"2010","journal-title":"Proteomics Clin Appl"},{"key":"10.1016\/j.jhep.2018.06.023_b0180","doi-asserted-by":"crossref","unstructured":"De Chiara F, Habtension A, Davies N, Andreola F, Rombouts K, Arias N, Thomsen KL, et al. Early increase in ammonia is a feature of Non-Alcoholic Fatty Liver Disease and the ammonia lowering drug, Ornithine Phenylacetate (OCR-002) prevents progression of fibrosis in a rodent model. Abstract, The International Liver Congress. 2017.","DOI":"10.1016\/S0168-8278(17)30620-7"}],"container-title":["Journal of Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0168827818321767?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0168827818321767?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T19:34:37Z","timestamp":1759174477000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0168827818321767"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,10]]},"references-count":36,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2018,10]]}},"alternative-id":["S0168827818321767"],"URL":"https:\/\/doi.org\/10.1016\/j.jhep.2018.06.023","relation":{},"ISSN":["0168-8278"],"issn-type":[{"value":"0168-8278","type":"print"}],"subject":[],"published":{"date-parts":[[2018,10]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Urea cycle dysregulation in non-alcoholic fatty liver disease","name":"articletitle","label":"Article Title"},{"value":"Journal of Hepatology","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.jhep.2018.06.023","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.","name":"copyright","label":"Copyright"}]}}