{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T14:08:09Z","timestamp":1789135689431,"version":"build-2803163510"},"reference-count":39,"publisher":"American Chemical Society (ACS)","issue":"9","license":[{"start":{"date-parts":[[2026,8,15]],"date-time":"2026-08-15T00:00:00Z","timestamp":1786752000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000066","name":"National Institute of Environmental Health Sciences","doi-asserted-by":"publisher","award":["ES046571"],"award-info":[{"award-number":["ES046571"]}],"id":[{"id":"10.13039\/100000066","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":["DK109392"],"award-info":[{"award-number":["DK109392"]}],"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":["DK136599"],"award-info":[{"award-number":["DK136599"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Uridine 5\u2032-diphospho-glucuronosyltransferase (UGT) enzymes play a critical role in hepatic and other metabolism of endogenous and exogenous small molecules. The addition of glucuronic acid via UGT increases the polarity and subsequent solubility of small molecules, helping direct them for biliary excretion and renal excretion by organic anion transporter OAT3 (SLC22A8). Mutations in UGTs are associated with disorders in biliary metabolism (e.g., Gilbert\u2019s syndrome, Crigler-Najjar syndrome). Here, we used comprehensive serum metabolomic profiling of pan Ugt1-knockout (Ugt1\u2013\/\u2013) mice to define the metabolic consequences of UGT deficiency. All 7 knockout mice exhibited markedly elevated bilirubin (mean = 5.96 mg\/dL). Partial Least Squares Discriminant Analysis (PLS-DA) showed clear separation between Ugt1\u2013\/\u2013 and wild type (WT), and volcano plots revealed significant endogenous metabolite alterations. These included upregulation of numerous bilirubin degradation products as well as major disturbances in lipid and amino acid metabolism. In particular, pathway enrichment analyses identified disruptions in fatty acid biosynthesis, glycine-serine metabolism, heme breakdown, porphyrin metabolism, and \u03b2-oxidation of fatty acids. Thus, the UGT1 proteins regulate different aspects of endogenous metabolism and signaling. Consistent with this notion, there were increases in liver expression of several nuclear receptors (e.g., HNF4a, PPARa, PXR) involved in metabolic signaling. These results support the remote sensing and signaling theory (RSST), which proposes that UGT1 proteins play a key role in organ crosstalk via routing small molecules between the liver and kidney, with glucuronidated molecules being mainly directed to the multispecific SLC kidney transporter OAT3. We propose that this glucuronidation-regulated RSST loop is essential to signaling along the gut-liver-kidney axis.<\/jats:p>","DOI":"10.1021\/acsptsci.6c00197","type":"journal-article","created":{"date-parts":[[2026,8,15]],"date-time":"2026-08-15T05:01:17Z","timestamp":1786770077000},"page":"2535-2543","source":"Crossref","is-referenced-by-count":0,"title":["Regulation of Diverse\nEndogenous Metabolic and Signaling\nPathways by UDP-Glucuronosyltransferases (UGTs) Revealed by Metabolomics\nof Knockout Mice"],"prefix":"10.1021","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-6757-4118","authenticated-orcid":true,"given":"Kian","family":"Falah","sequence":"first","affiliation":[{"name":"University of California , , , ,","place":["La Jolla, California, United States, 92093"]},{"name":"University of California , , , ,","place":["La Jolla, California, United States, 92093"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiarun","family":"Liu","sequence":"additional","affiliation":[{"name":"University of California , , , ,","place":["La Jolla, California, United States, 92093"]},{"name":"University of California , , , ,","place":["La Jolla, California, United States, 92093"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nghia","family":"Nguyen","sequence":"additional","affiliation":[{"name":"University of California , , , ,","place":["La Jolla, California, United States, 92093"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shujuan","family":"Chen","sequence":"additional","affiliation":[{"name":"University of California , , , ,","place":["La Jolla, California, United States, 92093"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert H.","family":"Tukey","sequence":"additional","affiliation":[{"name":"University of California , , , ,","place":["La Jolla, California, United States, 92093"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjay K.","family":"Nigam","sequence":"additional","affiliation":[{"name":"University of California , , , ,","place":["La Jolla, California, United States, 92093"]},{"name":"University of California , , , ,","place":["La Jolla, California, United States, 92093"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,15]]},"reference":[{"issue":"1","key":"2026091109131906400_cit1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-15231-w","article-title":"Chemical Similarity Enrichment Analysis (ChemRICH) as alternative\nto biochemical pathway mapping for metabolomic datasets","volume":"7","author":"Barupal","year":"2017","journal-title":"Sci. Rep."},{"issue":"7","key":"2026091109131906400_cit2","doi-asserted-by":"publisher","first-page":"1136","DOI":"10.1093\/bioinformatics\/btu761","article-title":"XenoSite\nserver: a web-available\nsite of metabolism prediction tool","volume":"31","author":"Matlock","year":"2015","journal-title":"Bioinformatics."},{"issue":"2","key":"2026091109131906400_cit3","doi-asserted-by":"publisher","first-page":"1153","DOI":"10.1152\/physrev.00058.2017","article-title":"The UDP-Glycosyltransferase\n(UGT) Superfamily: New Members, New Functions, and Novel Paradigms","volume":"99","author":"Meech","year":"2019","journal-title":"Physiol. Rev."},{"issue":"1","key":"2026091109131906400_cit4","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.dmpk.2017.10.002","article-title":"Species\ndifferences in drug glucuronidation:\nHumanized UDP-glucuronosyltransferase 1 mice and their application\nfor predicting drug glucuronidation and drug-induced toxicity in humans","volume":"33","author":"Fujiwara","year":"2018","journal-title":"Drug Metab. Pharmacokinet."},{"key":"2026091109131906400_cit5","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1016\/j.phrs.2017.05.001","article-title":"UDP-glucuronosyltransferases\n(UGTs) and their related metabolic cross-talk with internal homeostasis:\nA systematic review of UGT isoforms for precision medicine","volume":"121","author":"Yang","year":"2017","journal-title":"Pharmacol. Res."},{"key":"2026091109131906400_cit6","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2014.00349","article-title":"The UDP-glucuronosyltransferases\nof the blood-brain barrier: their role in drug metabolism and detoxication","volume":"8","author":"Ouzzine","year":"2014","journal-title":"Front. Cell. Neurosci."},{"issue":"5","key":"2026091109131906400_cit7","doi-asserted-by":"publisher","first-page":"691","DOI":"10.1016\/S0006-2952(03)00296-X","article-title":"Vertebrate\nUDP-glucuronosyltransferases: functional and evolutionary aspects","volume":"66","author":"Bock","year":"2003","journal-title":"Biochem. Pharmacol."},{"issue":"1","key":"2026091109131906400_cit8","doi-asserted-by":"publisher","DOI":"10.1186\/s12936-019-2705-2","article-title":"UDP-glycosyltransferase\ngenes and\ntheir association and mutations associated with pyrethroid resistance\nin Anopheles sinensis (Diptera: Culicidae)","volume":"18","author":"Zhou","year":"2019","journal-title":"Malar J."},{"key":"2026091109131906400_cit9","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/j.ibmb.2014.04.003","article-title":"Bacterial\norigin of a diverse family of UDP-glycosyltransferase genes in the\nTetranychus urticae genome","volume":"50","author":"Ahn","year":"2014","journal-title":"Insect Biochem.\nMol. Biol."},{"key":"2026091109131906400_cit10","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.bcp.2015.10.001","article-title":"The UDP-glycosyltransferase\n(UGT) superfamily expressed in humans, insects and plants: Animal-plant\narms-race and co-evolution","volume":"99","author":"Bock","year":"2016","journal-title":"Biochem. Pharmacol."},{"issue":"1","key":"2026091109131906400_cit11","doi-asserted-by":"publisher","first-page":"24","DOI":"10.3109\/03602530903210682","article-title":"UGT genomic diversity: beyond gene\nduplication","volume":"42","author":"Guillemette","year":"2010","journal-title":"Drug Metab. Rev."},{"issue":"6","key":"2026091109131906400_cit12","doi-asserted-by":"publisher","first-page":"771","DOI":"10.1016\/j.bcp.2010.04.034","article-title":"Functions\nand transcriptional regulation of adult human hepatic UDP-glucuronosyl-transferases\n(UGTs): mechanisms responsible for interindividual variation of UGT\nlevels","volume":"80","author":"Bock","year":"2010","journal-title":"Biochem. Pharmacol."},{"issue":"9","key":"2026091109131906400_cit13","doi-asserted-by":"publisher","first-page":"1277","DOI":"10.1038\/s41416-019-0722-0","article-title":"Emerging roles\nfor UDP-glucuronosyltransferases in drug resistance and cancer progression","volume":"122","author":"Allain","year":"2020","journal-title":"Br J. Cancer"},{"issue":"3","key":"2026091109131906400_cit14","doi-asserted-by":"publisher","first-page":"282","DOI":"10.1080\/03602532.2022.2083632","article-title":"The role of\nUDP-glycosyltransferases in xenobioticresistance","volume":"54","author":"Dimunova\u0301","year":"2022","journal-title":"Drug Metab. Rev."},{"issue":"2","key":"2026091109131906400_cit15","doi-asserted-by":"publisher","first-page":"104","DOI":"10.2174\/138920011795016872","article-title":"Regulation of phase II biotransformation\nenzymes by steroid hormones","volume":"12","author":"Kohalmy","year":"2011","journal-title":"Curr. Drug Metab."},{"issue":"7","key":"2026091109131906400_cit16","doi-asserted-by":"publisher","first-page":"1071","DOI":"10.1124\/dmd.115.063719","article-title":"Expression of UDP-Glucuronosyltransferase\n1 (UGT1) and Glucuronidation Activity toward Endogenous Substances\nin Humanized UGT1Mouse Brain","volume":"43","author":"Kutsuno","year":"2015","journal-title":"Drug Metab. Dispos."},{"issue":"1","key":"2026091109131906400_cit17","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1124\/dmd.106.012070","article-title":"Tissue- and gender-specific mRNA expression of UDP-glucuronosyltransferases\n(UGTs) in mice","volume":"35","author":"Buckley","year":"2007","journal-title":"Drug Metab. Dispos."},{"issue":"2","key":"2026091109131906400_cit18","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1124\/dmd.112.049197","article-title":"Tissue distribution and relative\ngene expression of UDP-glucuronosyltransferases (2B7, 2B15, 2B17)\nin the human fetus","volume":"41","author":"Ekstro\u0308m","year":"2013","journal-title":"Drug Metab. Dispos."},{"issue":"45","key":"2026091109131906400_cit19","doi-asserted-by":"publisher","first-page":"37547","DOI":"10.1074\/jbc.M506683200","article-title":"Tissue-specific,\ninducible, and hormonal control of the human UDP-glucuronosyltransferase-1\n(UGT1) locus","volume":"280","author":"Chen","year":"2005","journal-title":"J. Biol. Chem."},{"issue":"3","key":"2026091109131906400_cit20","doi-asserted-by":"publisher","first-page":"249","DOI":"10.2174\/1389200033489442","article-title":"Regulation\nof UDP glucuronosyltransferase genes","volume":"4","author":"Mackenzie","year":"2003","journal-title":"Curr.\nDrug Metab."},{"key":"2026091109131906400_cit21","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2016.00437","article-title":"Age-Dependent Hepatic UDP-Glucuronosyltransferase\nGene Expression\nand Activity in Children","volume":"7","author":"Neumann","year":"2016","journal-title":"Front. Pharmacol."},{"issue":"3","key":"2026091109131906400_cit22","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1124\/mol.109.056564","article-title":"Toward a systems\nlevel understanding of organic anion\nand other multispecific drug transporters: a remote sensing and signaling\nhypothesis","volume":"76","author":"Ahn","year":"2009","journal-title":"Mol. Pharmacol."},{"issue":"5","key":"2026091109131906400_cit23","doi-asserted-by":"publisher","first-page":"795","DOI":"10.1124\/mol.110.070607","article-title":"Remote communication through solute\ncarriers and ATP binding cassette drug transporter pathways: an update\non the remote sensing and signaling hypothesis","volume":"79","author":"Wu","year":"2011","journal-title":"Mol. Pharmacol."},{"issue":"1","key":"2026091109131906400_cit24","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1038\/nrd4461","article-title":"What do\ndrug transporters really do?","volume":"14","author":"Nigam","year":"2015","journal-title":"Nat. Rev. Drug\nDiscovery"},{"key":"2026091109131906400_cit25","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2024.108723","article-title":"Organic anion transporters in remote sensing and organ\ncrosstalk","volume":"263","author":"Granados","year":"2024","journal-title":"Pharmacol. Ther."},{"issue":"4","key":"2026091109131906400_cit26","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1002\/1098-1004(200010)16:4&lt;297::AID-HUMU2&gt;3.0.CO;2-Z","article-title":"Genetic\nlesions of bilirubin uridine-diphosphoglucuronate\nglucuronosyltransferase (UGT1A1) causing Crigler-Najjar and Gilbert\nsyndromes: correlation of genotype to phenotype","volume":"16","author":"Kadakol","year":"2000","journal-title":"Hum. Mutat."},{"issue":"3","key":"2026091109131906400_cit27","doi-asserted-by":"publisher","DOI":"10.1002\/humu.9322","article-title":"Spectrum of UGT1A1 mutations in Crigler-Najjar\n(CN) syndrome patients: identification of twelve novel alleles and\ngenotype-phenotype correlation","volume":"25","author":"Servedio","year":"2005","journal-title":"Hum. Mutat."},{"issue":"12","key":"2026091109131906400_cit28","doi-asserted-by":"publisher","first-page":"7901","DOI":"10.1074\/jbc.M709244200","article-title":"Disruption\nof the ugt1 locus in mice resembles human Crigler-Najjar type I disease","volume":"283","author":"Nguyen","year":"2008","journal-title":"J. Biol. Chem."},{"issue":"6","key":"2026091109131906400_cit29","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1007\/BF00206965","article-title":"Genetic heterogeneity\nof Crigler-Najjar\nsyndrome type I: a study of 14 cases","volume":"94","author":"Labrune","year":"1994","journal-title":"Hum. Genet."},{"issue":"16","key":"2026091109131906400_cit30","doi-asserted-by":"publisher","first-page":"6656","DOI":"10.1021\/ac901536h","article-title":"Integrated,\nnontargeted ultrahigh performance liquid chromatography\/electrospray\nionization tandem mass spectrometry platform for the identification\nand relative quantification of the small-molecule complement of biological\nsystems","volume":"81","author":"Evans","year":"2009","journal-title":"Anal. Chem."},{"issue":"4","key":"2026091109131906400_cit31","doi-asserted-by":"publisher","first-page":"521","DOI":"10.1177\/0192623309336152","article-title":"Untargeted\nMetabolomic Profiling as an Evaluative Tool of Fenofibrate-Induced\nToxicology in Fischer 344 Male Rats","volume":"37","author":"Ohta","year":"2009","journal-title":"Toxicol.\nPathol."},{"issue":"4","key":"2026091109131906400_cit32","doi-asserted-by":"publisher","first-page":"383","DOI":"10.2217\/14622416.9.4.383","article-title":"Analysis\nof the adult human plasma metabolome","volume":"9","author":"Lawton","year":"2008","journal-title":"Pharmacogenomics"},{"issue":"W1","key":"2026091109131906400_cit33","doi-asserted-by":"publisher","first-page":"W398","DOI":"10.1093\/nar\/gkae253","article-title":"MetaboAnalyst 6.0: towards a unified platform for metabolomics data\nprocessing, analysis and interpretation","volume":"52","author":"Pang","year":"2024","journal-title":"Nucleic\nAcids Res."},{"issue":"4","key":"2026091109131906400_cit34","doi-asserted-by":"publisher","first-page":"798S","DOI":"10.3945\/an.115.011221","article-title":"Leucine Metabolism in T Cell Activation:\nmTOR Signaling and Beyond","volume":"7","author":"Ananieva","year":"2016","journal-title":"Adv. Nutr."},{"issue":"12","key":"2026091109131906400_cit35","doi-asserted-by":"publisher","first-page":"3373","DOI":"10.1021\/ci400518g","article-title":"XenoSite: accurately predicting CYP-mediated\nsites of metabolism with neural networks","volume":"53","author":"Zaretzki","year":"2013","journal-title":"J.\nChem. Inf. Model."},{"issue":"D1","key":"2026091109131906400_cit36","doi-asserted-by":"publisher","first-page":"D622","DOI":"10.1093\/nar\/gkab1062","article-title":"HMDB 5.0: the Human Metabolome Database\nfor 2022","volume":"50","author":"Wishart","year":"2022","journal-title":"Nucleic Acids Res."},{"issue":"11","key":"2026091109131906400_cit37","doi-asserted-by":"publisher","first-page":"5024","DOI":"10.1073\/pnas.0913290107","article-title":"Developmental\nhyperbilirubinemia\nand CNS toxicity in mice humanized with the UDP glucuronosyltransferase\n1 (UGT1) locus","volume":"107","author":"Fujiwara","year":"2010","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2026091109131906400_cit38","first-page":"149","article-title":"Gunn rat: a model for inherited deficiency\nof bilirubin glucuronidation","volume":"37","author":"Chowdhury","year":"1993","journal-title":"Adv. Vet. Sci.\nComp. Med."},{"issue":"1","key":"2026091109131906400_cit39","doi-asserted-by":"publisher","first-page":"123","DOI":"10.3109\/03602530903208983","article-title":"Use of transgenic mice\nin UDP-glucuronosyltransferase (UGT) studies","volume":"42","author":"Ou","year":"2010","journal-title":"Drug Metab. Rev."}],"container-title":["ACS Pharmacology &amp; Translational\nScience"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acsptsci.6c00197","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/aptsfn\/article-pdf\/9\/9\/2535\/66587364\/acsptsci.6c00197.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/aptsfn\/article-pdf\/9\/9\/2535\/66587364\/acsptsci.6c00197.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T13:24:20Z","timestamp":1789133060000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/aptsfn\/article\/9\/9\/2535\/5258167\/Regulation-of-Diverse-Endogenous-Metabolic-and"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,15]]},"references-count":39,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,8,15]]},"published-print":{"date-parts":[[2026,9,11]]}},"URL":"https:\/\/doi.org\/10.1021\/acsptsci.6c00197","relation":{},"ISSN":["2575-9108"],"issn-type":[{"value":"2575-9108","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,15]]}}}