{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T15:48:33Z","timestamp":1787500113807,"version":"build-2736575974"},"reference-count":39,"publisher":"Ovid Technologies (Wolters Kluwer Health)","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"abstract":"<jats:sec xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">The Fontan operation is the current standard of care for single\u2010ventricle congenital heart disease. Almost all patients with Fontan operation develop liver fibrosis at a young age, known as Fontan\u2010associated liver disease (FALD). The pathogenesis and mechanisms underlying FALD remain little understood, and there are no effective therapies. We aimed to present a comprehensive multiomic analysis of human FALD, revealing the fundamental biology and pathogenesis of FALD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods and Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">We recently generated a single\u2010cell transcriptomic and epigenomic atlas of human FALD using single\u2010nucleus multiomic RNA sequencing and assay for transposase\u2010accessible chromatin using sequencing, which uncovered substantial metabolic reprogramming. Here, we applied liquid chromatography\u2013mass spectrometry\u2013based untargeted metabolomics to unveil the metabolomic landscape of human FALD, using liver samples\/biopsies from age\u2010 and sex\u2010matched donors and patients with FALD (n=12 per group). Results were integrated with liver single\u2010nucleus multiomic RNA sequencing and assay for transposase\u2010accessible chromatin using sequencing and serum metabolomics data to present a comprehensive multiomic atlas of FALD.We discovered significant metabolic abnormalities in livers of adolescent patients with Fontan circulation, particularly amino acid metabolism, peroxisomal fatty acid oxidation, cytochrome P450 system, glycolysis, tricarboxylic acid cycle, ketone body metabolism, and bile acid metabolism. Integrated analyses with liver single\u2010nucleus multiomic RNA sequencing and assay for transposase\u2010accessible chromatin using sequencing results unveiled potential underlying mechanisms of these metabolic changes. Comparison with serum metabolomics data indicate that liver metabolic reprogramming contributes to circulatory metabolomic changes in FALD. Furthermore, comparison with metabolomics data of human metabolic dysfunction\u2013associated fatty liver disease and metabolic dysfunction\u2013associated steatohepatitis highlighted dysregulated amino acid metabolism as a common metabolic abnormality.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">Our comprehensive multiomic analyses reveal new insights into the fundamental biology and pathogenesis mechanisms of human FALD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/jaha.124.039201","type":"journal-article","created":{"date-parts":[[2025,3,7]],"date-time":"2025-03-07T23:44:46Z","timestamp":1741391086000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":8,"title":["Comprehensive Multiomic Analysis Reveals Metabolic Reprogramming Underlying Human Fontan\u2010Associated Liver Disease"],"prefix":"10.1161","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9759-0809","authenticated-orcid":false,"given":"Rasheed","family":"Sule","sequence":"first","affiliation":[{"name":"Center for Mitochondrial and Epigenomic Medicine Children\u2019s Hospital of Philadelphia Philadelphia PA USA"},{"name":"Cardiovascular Institute, Children\u2019s Hospital of Philadelphia Philadelphia PA USA"},{"name":"Department of Pathology and Laboratory Medicine Children\u2019s Hospital of Philadelphia Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2422-1652","authenticated-orcid":false,"given":"Po","family":"Hu","sequence":"additional","affiliation":[{"name":"Center for Mitochondrial and Epigenomic Medicine Children\u2019s Hospital of Philadelphia Philadelphia PA USA"},{"name":"Cardiovascular Institute, Children\u2019s Hospital of Philadelphia Philadelphia PA USA"},{"name":"Department of Pathology and Laboratory Medicine Children\u2019s Hospital of Philadelphia Philadelphia PA USA"},{"name":"Department of Pathology and Laboratory Medicine Perelman School of Medicine, University of Pennsylvania Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clarissa","family":"Shoffler","sequence":"additional","affiliation":[{"name":"Cardiovascular Institute, Perelman School of Medicine University of Pennsylvania Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5003-0951","authenticated-orcid":false,"given":"Christopher","family":"Petucci","sequence":"additional","affiliation":[{"name":"Cardiovascular Institute, Perelman School of Medicine University of Pennsylvania Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1797-7323","authenticated-orcid":false,"given":"Benjamin J.","family":"Wilkins","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Children\u2019s Hospital of Philadelphia Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jack","family":"Rychik","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Children\u2019s Hospital of Philadelphia Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1924-0333","authenticated-orcid":false,"given":"Liming","family":"Pei","sequence":"additional","affiliation":[{"name":"Center for Mitochondrial and Epigenomic Medicine Children\u2019s Hospital of Philadelphia Philadelphia PA USA"},{"name":"Cardiovascular Institute, Children\u2019s Hospital of Philadelphia Philadelphia PA USA"},{"name":"Department of Pathology and Laboratory Medicine Children\u2019s Hospital of Philadelphia Philadelphia PA USA"},{"name":"Cardiovascular Institute, Perelman School of Medicine University of Pennsylvania Philadelphia PA USA"},{"name":"Department of Pathology and Laboratory Medicine Perelman School of Medicine, University of Pennsylvania Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2025,3,7]]},"reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIR.0000000000000696"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.120.045597"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.116.004809"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00246-012-0315-7"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2017.12.054"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2017.12.053"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehad788"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1111\/ctr.15302"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2023.03.421"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2023.1100514"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2023.12.005"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.adk6213"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11306-021-01846-8"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-65852-x"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1177\/2040622320916031"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcha.2021.100921"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00246-012-0274-z"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2012.11.073"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2015.12.038"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ahj.2019.07.013"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.111809"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-48009-6"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.316802.118"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00246-022-02930-z"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2022.115074"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/0005-2760(93)90224-w"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbalip.2013.06.007"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2020.165720"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2014.01.002"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.3390\/jox11030007"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1002\/cphy.c130024"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1021\/pr200629p"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v23.i15.2685"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1097\/MOP.0000000000000804"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2023.07.013"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a040584"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-023-01569-3"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aaz2841"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2020.10.026"}],"container-title":["Journal of the American Heart Association"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/JAHA.124.039201","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,7]],"date-time":"2025-03-07T23:44:48Z","timestamp":1741391088000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/JAHA.124.039201"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,7]]},"references-count":39,"alternative-id":["10.1161\/JAHA.124.039201"],"URL":"https:\/\/doi.org\/10.1161\/jaha.124.039201","relation":{},"ISSN":["2047-9980"],"issn-type":[{"value":"2047-9980","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,7]]},"assertion":[{"value":"2024-09-29","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-01-24","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-03-07","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e039201"}}