{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T18:05:53Z","timestamp":1784657153079,"version":"3.55.0"},"reference-count":44,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T00:00:00Z","timestamp":1784592000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["23SCEFIA1156649"],"award-info":[{"award-number":["23SCEFIA1156649"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["24DIVSUP1291162"],"award-info":[{"award-number":["24DIVSUP1291162"]}],"id":[{"id":"10.13039\/100000968","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":["DK099257"],"award-info":[{"award-number":["DK099257"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100016532","name":"Johns Hopkins All Children\u2019s Foundation","doi-asserted-by":"publisher","award":["ACRI fellowship"],"award-info":[{"award-number":["ACRI fellowship"]}],"id":[{"id":"10.13039\/100016532","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>Amino acid (AA) catabolism and ureagenesis in the liver are essential for maintaining systemic nitrogen homeostasis. Patients with Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) exhibit impaired hepatic AA catabolism and urea production, accompanied by repression of genes governing these pathways. The molecular basis of this repression remains unknown. Here, we identify the hepatocyte-specific long noncoding RNA hLMR1 as a key suppressor of hepatic AA catabolism. Using a humanized liver mouse model, we show that hLMR1 knockdown broadly upregulates genes involved in AA degradation and ureagenesis. Chromatin isolation by RNA purification (ChIRP) coupled with RNA-seq reveals extensive interactions between hLMR1 and the pre-mRNAs of AA catabolism genes, mediated by a complementary motif within hLMR1 (nucleotides 587\u2013598). In primary human hepatocytes, hLMR1 overexpression inhibits glucagon-induced activation of AA catabolic genes, whereas deletion of the 587\u2013598 region abrogates this effect. Analysis of human liver RNA-seq datasets demonstrates a negative correlation between hLMR1 expression and AA catabolic gene programs in MASLD. Together, these findings uncover hLMR1 as a previously unrecognized regulator of hepatic nitrogen metabolism, linking lncRNA dysregulation to metabolic dysfunction in MASLD.<\/jats:p>","DOI":"10.1371\/journal.pone.0353674","type":"journal-article","created":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T17:43:24Z","timestamp":1784655804000},"page":"e0353674","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["hLMR1, a hepatocyte-specific long noncoding RNA that represses amino acid catabolism through pre-mRNA interaction in human liver"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3479-4844","authenticated-orcid":true,"given":"Marcos E.","family":"Jaso-Vera","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shohei","family":"Takaoka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lanuza A.P.","family":"Faccioli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiping","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandro","family":"Soto-Gutierrez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7333-9561","authenticated-orcid":true,"given":"Xiangbo","family":"Ruan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,7,21]]},"reference":[{"issue":"3","key":"pone.0353674.ref001","doi-asserted-by":"crossref","DOI":"10.1152\/ajpendo.00045.2017","article-title":"Glucagon\u2019s effect on liver protein metabolism in vivo","volume":"313","author":"G Kraft","year":"2017","journal-title":"Am J Physiol Endocrinol Metab"},{"issue":"11","key":"pone.0353674.ref002","doi-asserted-by":"crossref","first-page":"2094","DOI":"10.1111\/liv.14205","article-title":"Non-alcoholic fatty liver disease alters expression of genes governing hepatic nitrogen conversion","volume":"39","author":"PL Eriksen","year":"2019","journal-title":"Liver Int"},{"issue":"1","key":"pone.0353674.ref003","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1002\/hep.29465","article-title":"Altered amino acid concentrations in NAFLD: Impact of obesity and insulin resistance","volume":"67","author":"M Gaggini","year":"2018","journal-title":"Hepatology"},{"issue":"12","key":"pone.0353674.ref004","doi-asserted-by":"crossref","first-page":"4049","DOI":"10.3390\/jcm9124049","article-title":"The Vicious Circle of Hepatic Glucagon Resistance in Non-Alcoholic Fatty Liver Disease","volume":"9","author":"KD Galsgaard","year":"2020","journal-title":"J Clin Med"},{"issue":"5","key":"pone.0353674.ref005","doi-asserted-by":"crossref","first-page":"1450","DOI":"10.3390\/nu12051450","article-title":"Changed Amino Acids in NAFLD and Liver Fibrosis: A Large Cross-Sectional Study without Influence of Insulin Resistance","volume":"12","author":"T Hasegawa","year":"2020","journal-title":"Nutrients"},{"key":"pone.0353674.ref006","doi-asserted-by":"crossref","first-page":"934847","DOI":"10.3389\/fendo.2022.934847","article-title":"Key hepatic signatures of human and mouse nonalcoholic steatohepatitis: A transcriptome-proteome data meta-analysis","volume":"13","author":"JJ Pyo","year":"2022","journal-title":"Front Endocrinol (Lausanne)"},{"issue":"6","key":"pone.0353674.ref007","article-title":"Interrupted Glucagon Signaling Reveals Hepatic \u03b1 Cell Axis and Role for L-Glutamine in \u03b1 Cell Proliferation","volume":"25","author":"ED Dean","year":"2017","journal-title":"Cell Metab"},{"issue":"3","key":"pone.0353674.ref008","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1016\/j.celrep.2015.06.034","article-title":"Glucagon Couples Hepatic Amino Acid Catabolism to mTOR-Dependent Regulation of \u03b1-Cell Mass","volume":"12","author":"MJ Solloway","year":"2015","journal-title":"Cell Rep"},{"issue":"6","key":"pone.0353674.ref009","doi-asserted-by":"crossref","first-page":"1090","DOI":"10.2337\/db19-0715","article-title":"Glucagon Resistance at the Level of Amino Acid Turnover in Obese Subjects With Hepatic Steatosis","volume":"69","author":"MP Suppli","year":"2020","journal-title":"Diabetes"},{"issue":"1","key":"pone.0353674.ref010","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1038\/s42255-018-0004-9","article-title":"The long noncoding RNA CHROME regulates cholesterol homeostasis in primate","volume":"1","author":"EJ Hennessy","year":"2019","journal-title":"Nat Metab"},{"issue":"3","key":"pone.0353674.ref011","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1016\/j.cmet.2015.02.004","article-title":"A liver-enriched long non-coding RNA, lncLSTR, regulates systemic lipid metabolism in mice","volume":"21","author":"P Li","year":"2015","journal-title":"Cell Metab"},{"issue":"1","key":"pone.0353674.ref012","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.molmet.2016.10.010","article-title":"Conserved function of the long noncoding RNA Blnc1 in brown adipocyte differentiation","volume":"6","author":"L Mi","year":"2016","journal-title":"Mol Metab"},{"issue":"8","key":"pone.0353674.ref013","doi-asserted-by":"crossref","first-page":"1867","DOI":"10.1016\/j.celrep.2016.01.062","article-title":"A long non-coding RNA, lncLGR, regulates hepatic glucokinase expression and glycogen storage during fasting","volume":"14","author":"X Ruan","year":"2016","journal-title":"Cell Rep"},{"issue":"1","key":"pone.0353674.ref014","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/s41467-019-13688-z","article-title":"In vivo functional analysis of non-conserved human lncRNAs associated with cardiometabolic traits","volume":"11","author":"X Ruan","year":"2020","journal-title":"Nat Commun"},{"issue":"1","key":"pone.0353674.ref015","doi-asserted-by":"crossref","DOI":"10.1172\/JCI136336","article-title":"Identification of human long noncoding RNAs associated with nonalcoholic fatty liver disease and metabolic homeostasis","volume":"131","author":"X Ruan","year":"2021","journal-title":"J Clin Invest"},{"issue":"3","key":"pone.0353674.ref016","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1038\/nm.4479","article-title":"Transcriptional regulation of macrophage cholesterol efflux and atherogenesis by a long noncoding RNA","volume":"24","author":"T Sallam","year":"2018","journal-title":"Nat Med"},{"issue":"1","key":"pone.0353674.ref017","doi-asserted-by":"crossref","first-page":"3622","DOI":"10.1038\/s41467-018-05933-8","article-title":"LincRNA H19 protects from dietary obesity by constraining expression of monoallelic genes in brown fat","volume":"9","author":"E Schmidt","year":"2018","journal-title":"Nat Commun"},{"issue":"4","key":"pone.0353674.ref018","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1016\/j.cmet.2016.08.019","article-title":"Integrative Transcriptome Analyses of Metabolic Responses in Mice Define Pivotal LncRNA Metabolic Regulators","volume":"24","author":"L Yang","year":"2016","journal-title":"Cell Metab"},{"issue":"3","key":"pone.0353674.ref019","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1016\/j.molcel.2014.06.004","article-title":"A long noncoding RNA transcriptional regulatory circuit drives thermogenic adipocyte differentiation","volume":"55","author":"X-Y Zhao","year":"2014","journal-title":"Mol Cell"},{"issue":"3","key":"pone.0353674.ref020","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1016\/j.bbagen.2013.10.035","article-title":"Evolutionary conservation of long non-coding RNAs; sequence, structure, function","volume":"1840","author":"P Johnsson","year":"2014","journal-title":"Biochim Biophys Acta"},{"issue":"3","key":"pone.0353674.ref021","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1016\/j.bbrc.2011.01.042","article-title":"The reconstituted \u201chumanized liver\u201d in TK-NOG mice is mature and functional","volume":"405","author":"M Hasegawa","year":"2011","journal-title":"Biochem Biophys Res Commun"},{"issue":"15","key":"pone.0353674.ref022","doi-asserted-by":"crossref","first-page":"2114","DOI":"10.1093\/bioinformatics\/btu170","article-title":"Trimmomatic: a flexible trimmer for Illumina sequence data","volume":"30","author":"AM Bolger","year":"2014","journal-title":"Bioinformatics"},{"issue":"1","key":"pone.0353674.ref023","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","article-title":"STAR: ultrafast universal RNA-seq aligner","volume":"29","author":"A Dobin","year":"2013","journal-title":"Bioinformatics"},{"issue":"2","key":"pone.0353674.ref024","doi-asserted-by":"crossref","DOI":"10.1093\/gigascience\/giab008","article-title":"Twelve years of SAMtools and BCFtools","volume":"10","author":"P Danecek","year":"2021","journal-title":"Gigascience"},{"issue":"10","key":"pone.0353674.ref025","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gkt214","article-title":"The Subread aligner: fast, accurate and scalable read mapping by seed-and-vote","volume":"41","author":"Y Liao","year":"2013","journal-title":"Nucleic Acids Res"},{"issue":"12","key":"pone.0353674.ref026","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"MI Love","year":"2014","journal-title":"Genome Biol"},{"issue":"5","key":"pone.0353674.ref027","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1089\/omi.2011.0118","article-title":"clusterProfiler: an R package for comparing biological themes among gene clusters","volume":"16","author":"G Yu","year":"2012","journal-title":"OMICS"},{"key":"pone.0353674.ref028","article-title":"Chromatin isolation by RNA purification (ChIRP)","volume":"61","author":"C Chu","year":"2012","journal-title":"J Vis Exp"},{"issue":"17","key":"pone.0353674.ref029","doi-asserted-by":"crossref","DOI":"10.1093\/bioinformatics\/bty560","article-title":"fastp: an ultra-fast all-in-one FASTQ preprocessor","volume":"34","author":"S Chen","year":"2018","journal-title":"Bioinformatics"},{"issue":"9","key":"pone.0353674.ref030","doi-asserted-by":"crossref","DOI":"10.1186\/gb-2008-9-9-r137","article-title":"Model-based analysis of ChIP-Seq (MACS)","volume":"9","author":"Y Zhang","year":"2008","journal-title":"Genome Biol"},{"issue":"6","key":"pone.0353674.ref031","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1093\/bioinformatics\/btq033","article-title":"BEDTools: a flexible suite of utilities for comparing genomic features","volume":"26","author":"AR Quinlan","year":"2010","journal-title":"Bioinformatics"},{"issue":"4","key":"pone.0353674.ref032","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1016\/j.molcel.2010.05.004","article-title":"Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities","volume":"38","author":"S Heinz","year":"2010","journal-title":"Mol Cell"},{"issue":"1","key":"pone.0353674.ref033","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/nar\/28.1.27","article-title":"KEGG: kyoto encyclopedia of genes and genomes","volume":"28","author":"M Kanehisa","year":"2000","journal-title":"Nucleic Acids Res"},{"issue":"1","key":"pone.0353674.ref034","doi-asserted-by":"crossref","first-page":"2247576","DOI":"10.1080\/15476278.2023.2247576","article-title":"Human Hepatocellular response in Cholestatic Liver Diseases","volume":"19","author":"K Ortiz","year":"2023","journal-title":"Organogenesis"},{"issue":"1","key":"pone.0353674.ref035","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.jhep.2021.03.005","article-title":"A single cell gene expression atlas of 28 human livers","volume":"75","author":"J Brancale","year":"2021","journal-title":"J Hepatol"},{"issue":"4","key":"pone.0353674.ref036","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1016\/j.molcel.2011.08.027","article-title":"Genomic maps of long noncoding RNA occupancy reveal principles of RNA-chromatin interactions","volume":"44","author":"C Chu","year":"2011","journal-title":"Mol Cell"},{"issue":"7","key":"pone.0353674.ref037","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1210\/js.2018-00122","article-title":"Transcriptomic Profiling of Obesity-Related Nonalcoholic Steatohepatitis Reveals a Core Set of Fibrosis-Specific Genes","volume":"2","author":"GS Gerhard","year":"2018","journal-title":"J Endocr Soc"},{"issue":"3","key":"pone.0353674.ref038","doi-asserted-by":"crossref","DOI":"10.1016\/j.cmet.2018.01.005","article-title":"An Integrated Understanding of the Rapid Metabolic Benefits of a Carbohydrate-Restricted Diet on Hepatic Steatosis in Humans","volume":"27","author":"A Mardinoglu","year":"2018","journal-title":"Cell Metab"},{"issue":"1","key":"pone.0353674.ref039","doi-asserted-by":"crossref","DOI":"10.1152\/ajpgi.00216.2017","article-title":"Hyperglucagonemia correlates with plasma levels of non-branched-chain amino acids in patients with liver disease independent of type 2 diabetes","volume":"314","author":"NJ Wewer Albrechtsen","year":"2018","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"issue":"7","key":"pone.0353674.ref040","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1007\/s00439-024-02654-5","article-title":"Integrative regulation of hLMR1 by dietary and genetic factors in nonalcoholic fatty liver disease and hyperlipidemia","volume":"143","author":"ME Jaso-Vera","year":"2024","journal-title":"Hum Genet"},{"issue":"5","key":"pone.0353674.ref041","article-title":"The long noncoding RNA SPRIGHTLY acts as an intranuclear organizing hub for pre-mRNA molecules","volume":"3","author":"B Lee","year":"2017","journal-title":"Sci Adv"},{"issue":"18","key":"pone.0353674.ref042","doi-asserted-by":"crossref","DOI":"10.1016\/j.cell.2023.07.017","article-title":"Humanized mouse liver reveals endothelial control of essential hepatic metabolic functions","volume":"186","author":"E Kaffe","year":"2023","journal-title":"Cell"},{"issue":"2","key":"pone.0353674.ref043","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1016\/j.jcmgh.2021.10.007","article-title":"A Novel Humanized Model of NASH and Its Treatment With META4, A Potent Agonist of MET","volume":"13","author":"J Ma","year":"2022","journal-title":"Cell Mol Gastroenterol Hepatol"},{"key":"pone.0353674.ref044","doi-asserted-by":"crossref","DOI":"10.1161\/circ.144.suppl_1.10979","article-title":"Abstract 10979: Liver-Humanized Mice Provide a New Platform to Study Human Cardiometabolic Diseases","volume":"144","author":"ME Minniti","year":"2021","journal-title":"Circulation"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0353674","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T17:43:35Z","timestamp":1784655815000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0353674"}},"subtitle":[],"editor":[{"given":"Rongchun","family":"Han","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,7,21]]},"references-count":44,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,7,21]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0353674","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,21]]}}}