{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T10:23:26Z","timestamp":1791195806689,"version":"4.1.0"},"reference-count":58,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2019,8,1]],"date-time":"2019-08-01T00:00:00Z","timestamp":1564617600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["K01DK076846"],"award-info":[{"award-number":["K01DK076846"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["R01DK064913"],"award-info":[{"award-number":["R01DK064913"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Inher Metab Disea"],"published-print":{"date-parts":[[2019,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Abundance of urea cycle enzymes in the liver is regulated by dietary protein intake. Although urea cycle enzyme levels rise in response to a high\u2010protein (HP) diet, signaling networks that sense dietary protein intake and trigger changes in expression of urea cycle genes have not been identified. The aim of this study was to identify signaling pathway(s) that respond to changes in protein intake and regulate expression of urea cycle genes in mice and human hepatocytes. Mice were adapted to either HP or low\u2010protein diets followed by isolation of liver protein and mRNA and integrated analysis of the proteomic and transcriptomic data. HP diet led to increased expression of mRNA and enzymes in amino acid degradation pathways and decreased expression of mRNA and enzymes in carbohydrate and fat metabolism, which implicated adenosine monophosphate\u2010activated protein kinase (AMPK) as a possible regulator. Primary human hepatocytes, treated with 5\u2010aminoimidazole\u20104\u2010carboxamide ribonucleotide (AICAR) an activator of AMPK, were used to test whether AMPK regulates expression of urea cycle genes. The abundance of carbamoylphosphate synthetase 1 and ornithine transcarbamylase mRNA increased in hepatocytes treated with AICAR, which supports a role for AMPK signaling in regulation of the urea cycle. Because AMPK is either a target of drugs used to treat type\u20102 diabetes, these drugs might increase the expression of urea cycle enzymes in patients with partial urea cycle disorders, which could be the basis of a new therapeutic approach.<\/jats:p>","DOI":"10.1002\/jimd.12133","type":"journal-article","created":{"date-parts":[[2019,6,9]],"date-time":"2019-06-09T02:44:07Z","timestamp":1560048247000},"page":"1088-1096","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["AMP\u2010activated protein kinase signaling regulated expression of urea cycle enzymes in response to changes in dietary protein intake"],"prefix":"10.1002","volume":"42","author":[{"given":"Sandra K.","family":"Heibel","sequence":"first","affiliation":[{"name":"Center for Genetic Medicine Research Children's National Medical Center  Washington District of Columbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J.","family":"McGuire","sequence":"additional","affiliation":[{"name":"Medical Genomics and Metabolic Genetics Branch National Human Genome Research Institute  Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nantaporn","family":"Haskins","sequence":"additional","affiliation":[{"name":"Center for Genetic Medicine Research Children's National Medical Center  Washington District of Columbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Himani D.","family":"Majumdar","sequence":"additional","affiliation":[{"name":"Center for Genetic Medicine Research Children's National Medical Center  Washington District of Columbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sree","family":"Rayavarapu","sequence":"additional","affiliation":[{"name":"Center for Genetic Medicine Research Children's National Medical Center  Washington District of Columbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanneboyina","family":"Nagaraju","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences Binghamton University  Binghamton New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yetrib","family":"Hathout","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences Binghamton University  Binghamton New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristy","family":"Brown","sequence":"additional","affiliation":[{"name":"Center for Genetic Medicine Research Children's National Medical Center  Washington District of Columbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mendel","family":"Tuchman","sequence":"additional","affiliation":[{"name":"Center for Genetic Medicine Research Children's National Medical Center  Washington District of Columbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9140-5585","authenticated-orcid":false,"given":"Ljubica","family":"Caldovic","sequence":"additional","affiliation":[{"name":"Center for Genetic Medicine Research Children's National Medical Center  Washington District of Columbia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,8]]},"reference":[{"key":"e_1_2_9_2_1","volume-title":"The Metabolic & Molecular Bases of Inherited Disease","author":"Brusilow SW","year":"2001"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.1990.70.3.701"},{"key":"e_1_2_9_4_1","volume-title":"GeneReviews\u00ae","author":"Ah Mew N","year":"1993"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2014.08.001"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2009.11.014"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20146"},{"key":"e_1_2_9_8_1","first-page":"395","article-title":"Stupor in an adolescent following Yom Kippur fast, due to late\u2010onset ornithine transcarbamylase deficiency","volume":"10","author":"Marcus N","year":"2008","journal-title":"Isr Med Assoc J"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1017\/S0317167100018205"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-6143.2006.01680.x"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00134-008-1217-2"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.1997.79"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2013.09.003"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-277X.2012.01259.x"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1172-7-32"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.172.3987.1042"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4757-6903-6_32"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)93943-8"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)73959-3"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432-1033.1979.tb13082.x"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1177\/117762500800200001"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1042\/bj0940410"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/0003-9861(87)90479-6"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1210\/mend-2-5-444"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)81251-0"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(17)40885-4"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1006\/abbi.1993.1139"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432-1033.1990.tb19275.x"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.18.11.6305"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M007001200"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.49.31243"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0029527"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.3727\/096368911X600939"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1093\/ajcn\/87.5.1558S"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.physbeh.2008.01.003"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1079\/BJN19740088"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/0003-9861(87)90455-3"},{"key":"e_1_2_9_38_1","volume-title":"GeneReviews\u00ae","author":"Shchelochkov OA","year":"1993"},{"key":"e_1_2_9_39_1","volume-title":"GeneReviews\u00ae","author":"Strauss KA","year":"1993"},{"key":"e_1_2_9_40_1","volume-title":"GeneReviews\u00ae","author":"Manoli I","year":"1993"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M703701200"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbalip.2004.12.001"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2008.61"},{"key":"e_1_2_9_44_1","first-page":"2634","article-title":"Modulation of rat liver 3\u2010hydroxy\u20103\u2010methylglutaryl\u2010CoA reductase activity by reversible phosphorylation","volume":"41","author":"Beg ZH","year":"1982","journal-title":"Fed Proc"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(17)31770-2"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-5793(02)03501-9"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2007.11.038"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2005.10.003"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2091-9-24"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a019141"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1002\/mnfr.201100064"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature10798"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1606022113"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)34635-0"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0091921"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M606676200"},{"key":"e_1_2_9_57_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M410755200"},{"key":"e_1_2_9_58_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(17)36642-5"},{"key":"e_1_2_9_59_1","doi-asserted-by":"publisher","DOI":"10.1038\/emm.2016.16"}],"container-title":["Journal of Inherited Metabolic Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jimd.12133","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/jimd.12133","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jimd.12133","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,24]],"date-time":"2023-08-24T00:53:29Z","timestamp":1692838409000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jimd.12133"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,8]]},"references-count":58,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2019,11]]}},"alternative-id":["10.1002\/jimd.12133"],"URL":"https:\/\/doi.org\/10.1002\/jimd.12133","archive":["Portico"],"relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/439380","asserted-by":"object"}]},"ISSN":["0141-8955","1573-2665"],"issn-type":[{"value":"0141-8955","type":"print"},{"value":"1573-2665","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,8]]},"assertion":[{"value":"2018-10-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-06-05","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-08-01","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}