{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T10:41:04Z","timestamp":1788172864465,"version":"build-2803163510"},"reference-count":49,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"8","license":[{"start":{"date-parts":[[2017,9,11]],"date-time":"2017-09-11T00:00:00Z","timestamp":1505088000000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Hepatology Communications"],"published-print":{"date-parts":[[2017,10]]},"abstract":"<jats:p>Iron overload causes the generation of reactive oxygen species that can lead to lasting damage to the liver and other organs. The goal of this study was to identify genes that modify the toxicity of iron overload. We studied the effect of iron overload on the hepatic transcriptional and metabolomic profile in mouse models using a dietary model of iron overload and a genetic model, the hemojuvelin knockout mouse. We then evaluated the correlation of <jats:italic toggle=\"yes\">nicotinamide N\u2010methyltransferase (NNMT)<\/jats:italic> expression with body iron stores in human patients and the effect of <jats:italic toggle=\"yes\">NNMT<\/jats:italic> knockdown on gene expression and viability in primary mouse hepatocytes. We found that iron overload induced significant changes in the expression of genes and metabolites involved in glucose and nicotinamide metabolism and that <jats:italic toggle=\"yes\">NNMT<\/jats:italic>, an enzyme that methylates nicotinamide and regulates hepatic glucose and cholesterol metabolism, is one of the most strongly down\u2010regulated genes in the liver in both genetic and dietary iron overload. We found that hepatic <jats:italic toggle=\"yes\">NNMT<\/jats:italic> expression is inversely correlated with serum ferritin levels and serum transferrin saturation in patients who are obese, suggesting that body iron stores regulate human liver <jats:italic toggle=\"yes\">NNMT<\/jats:italic> expression. Furthermore, we demonstrated that adenoviral knockdown of <jats:italic toggle=\"yes\">NNMT<\/jats:italic> in primary mouse hepatocytes exacerbates iron\u2010induced hepatocyte toxicity and increases expression of transcriptional markers of oxidative and endoplasmic reticulum stress, while overexpression of <jats:italic toggle=\"yes\">NNMT<\/jats:italic> partially reversed these effects. <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: Iron overload alters glucose and nicotinamide transcriptional and metabolic pathways in mouse hepatocytes and decreases <jats:italic toggle=\"yes\">NNMT<\/jats:italic> expression, while <jats:italic toggle=\"yes\">NNMT<\/jats:italic> deficiency worsens the toxic effect of iron overload. For these reasons, <jats:italic toggle=\"yes\">NNMT<\/jats:italic> may be a drug target for the prevention of iron\u2010induced hepatotoxicity. (<jats:italic toggle=\"yes\">Hepatology Communications<\/jats:italic> 2017;1:803\u2013815)<\/jats:p>","DOI":"10.1002\/hep4.1083","type":"journal-article","created":{"date-parts":[[2017,9,11]],"date-time":"2017-09-11T14:42:58Z","timestamp":1505140978000},"page":"803-815","source":"Crossref","is-referenced-by-count":9,"title":["Nicotinamide N\u2010methyltransferase expression decreases in iron overload, exacerbating toxicity in mouse hepatocytes"],"prefix":"10.1097","volume":"1","author":[{"given":"Tiago","family":"Koppe","sequence":"first","affiliation":[{"name":"Division of Hematology\/Oncology"},{"name":"Cancer Research Institute, Beth Israel Deaconess Medical Center,Boston,MA"},{"name":"Department of Medicine,Harvard Medical School,Boston,MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bonnie","family":"Patchen","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology"},{"name":"Cancer Research Institute, Beth Israel Deaconess Medical Center,Boston,MA"},{"name":"Department of Medicine,Harvard Medical School,Boston,MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron","family":"Cheng","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology"},{"name":"Cancer Research Institute, Beth Israel Deaconess Medical Center,Boston,MA"},{"name":"Department of Medicine,Harvard Medical School,Boston,MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manoj","family":"Bhasin","sequence":"additional","affiliation":[{"name":"Department of Medicine,Harvard Medical School,Boston,MA"},{"name":"Division of Interdisciplinary Medicine and Biotechnology, Beth Israel Deaconess Medical Center,Boston,MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris","family":"Vulpe","sequence":"additional","affiliation":[{"name":"Department of Physiological Sciences,University of Florida,Gainesville,FL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert E.","family":"Schwartz","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Weill Cornell Medical School,New York,NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose Maria","family":"Moreno\u2010Navarrete","sequence":"additional","affiliation":[{"name":"Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigaci\u00f3 Biom\u00e8dica de Girona,Hospital de Girona Dr. Josep Trueta and Universitat de Girona,Girona,Spain"},{"name":"CIBER Fisopatologia de la Obesidad y Nutricion, Instituto de Salud Carlos III,Madrid,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose Manuel","family":"Fernandez\u2010Real","sequence":"additional","affiliation":[{"name":"Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigaci\u00f3 Biom\u00e8dica de Girona,Hospital de Girona Dr. Josep Trueta and Universitat de Girona,Girona,Spain"},{"name":"CIBER Fisopatologia de la Obesidad y Nutricion, Instituto de Salud Carlos III,Madrid,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pavlos","family":"Pissios","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Beth Israel Deaconess Medical Center,Boston,MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula G.","family":"Fraenkel","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology"},{"name":"Cancer Research Institute, Beth Israel Deaconess Medical Center,Boston,MA"},{"name":"Department of Medicine,Harvard Medical School,Boston,MA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2017,9,11]]},"reference":[{"key":"hep41083-bib-0001-20240114","first-page":"a011668","article-title":"Iron metabolism: interactions with normal and disordered erythropoiesis","volume":"2","year":"2012","journal-title":"Cold Spring Harb Perspect Med"},{"key":"hep41083-bib-0002-20240114","doi-asserted-by":"crossref","first-page":"2090","DOI":"10.1126\/science.1104742","article-title":"Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization","volume":"306","year":"2004","journal-title":"Science"},{"key":"hep41083-bib-0003-20240114","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/j.cmet.2005.10.010","article-title":"A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression","volume":"2","year":"2005","journal-title":"Cell Metab"},{"key":"hep41083-bib-0004-20240114","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1007\/s00109-009-0447-2","article-title":"Bone morphogenetic protein (BMP)\u2010responsive elements located in the proximal and distal hepcidin promoter are critical for its response to HJV\/BMP\/SMAD","volume":"87","year":"2009","journal-title":"J Mol Med (Berl)"},{"key":"hep41083-bib-0005-20240114","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1002\/hep.24359","article-title":"Serum and liver iron differently regulate the bone morphogenetic protein 6 (BMP6)\u2010SMAD signaling pathway in mice","volume":"54","year":"2011","journal-title":"Hepatology"},{"key":"hep41083-bib-0006-20240114","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1038\/ng1777","article-title":"Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression","volume":"38","year":"2006","journal-title":"Nat Genet"},{"key":"hep41083-bib-0007-20240114","doi-asserted-by":"crossref","first-page":"2180","DOI":"10.1172\/JCI25683","article-title":"Hemojuvelin is essential for dietary iron sensing, and its mutation leads to severe iron overload","volume":"115","year":"2005","journal-title":"J Clin Invest"},{"key":"hep41083-bib-0008-20240114","doi-asserted-by":"crossref","first-page":"12547","DOI":"10.1074\/jbc.M608788200","article-title":"Evidence that inhibition of hemojuvelin shedding in response to iron is mediated through neogenin","volume":"282","year":"2007","journal-title":"J Biol Chem"},{"key":"hep41083-bib-0009-20240114","doi-asserted-by":"crossref","first-page":"4103","DOI":"10.1182\/blood-2004-12-4844","article-title":"Hepcidin in iron overload disorders","volume":"105","year":"2005","journal-title":"Blood"},{"key":"hep41083-bib-0010-20240114","doi-asserted-by":"crossref","first-page":"2169","DOI":"10.2337\/dc14-3082","article-title":"Mechanisms linking glucose homeostasis and iron metabolism toward the onset and progression of type 2 diabetes","volume":"38","year":"2015","journal-title":"Diabetes Care"},{"key":"hep41083-bib-0011-20240114","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1111\/obr.12057","article-title":"The role of adipocytes in the modulation of iron metabolism in obesity","volume":"14","year":"2013","journal-title":"Obes Rev"},{"key":"hep41083-bib-0012-20240114","doi-asserted-by":"crossref","first-page":"1098","DOI":"10.1038\/ijo.2008.43","article-title":"Adiposity in women and children from transition countries predicts decreased iron absorption, iron deficiency and a reduced response to iron fortification","volume":"32","year":"2008","journal-title":"Int J Obes (Lond)"},{"key":"hep41083-bib-0013-20240114","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1038\/ijo.2012.145","article-title":"Overweight impairs efficacy of iron supplementation in iron\u2010deficient South African children: a randomized controlled intervention","volume":"37","year":"2013","journal-title":"Int J Obes (Lond)"},{"key":"hep41083-bib-0014-20240114","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1038\/ijo.2009.146","article-title":"Overweight children have higher circulating hepcidin concentrations and lower iron status but have dietary iron intakes and bioavailability comparable with normal weight children","volume":"33","year":"2009","journal-title":"Int J Obes (Lond)"},{"key":"hep41083-bib-0015-20240114","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1038\/oby.2009.319","article-title":"Elevated systemic hepcidin and iron depletion in obese premenopausal females","volume":"18","year":"2010","journal-title":"Obesity (Silver Spring)"},{"key":"hep41083-bib-0016-20240114","doi-asserted-by":"crossref","first-page":"1412","DOI":"10.1038\/sj.ijo.0803625","article-title":"Inflammation and iron deficiency in the hypoferremia of obesity","volume":"31","year":"2007","journal-title":"Int J Obes (Lond)"},{"key":"hep41083-bib-0017-20240114","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1136\/bmj.317.7160.727","article-title":"Relation between iron stores and non\u2010insulin dependent diabetes in men: case\u2010control study","volume":"317","year":"1998","journal-title":"BMJ"},{"key":"hep41083-bib-0018-20240114","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1146\/annurev.nutr.28.061807.155443","article-title":"Nicotinic acid, nicotinamide, and nicotinamide riboside: a molecular evaluation of NAD\u2009+\u2009precursor vitamins in human nutrition","volume":"28","year":"2008","journal-title":"Annu Rev Nutr"},{"key":"hep41083-bib-0019-20240114","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.ijpharm.2015.05.024","article-title":"Effects of formulation design on niacin therapeutics: mechanism of action, metabolism, and drug delivery","volume":"490","year":"2015","journal-title":"Int J Pharm"},{"key":"hep41083-bib-0020-20240114","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/j.cmet.2015.07.017","article-title":"NNMT: a bad actor in fat makes good in liver","volume":"22","year":"2015","journal-title":"Cell Metab"},{"key":"hep41083-bib-0021-20240114","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1038\/nature13198","article-title":"Nicotinamide N\u2010methyltransferase knockdown protects against diet\u2010induced obesity","volume":"508","year":"2014","journal-title":"Nature"},{"key":"hep41083-bib-0022-20240114","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1038\/nm.3882","article-title":"Nicotinamide N\u2010methyltransferase regulates hepatic nutrient metabolism through Sirt1 protein stabilization","volume":"21","year":"2015","journal-title":"Nat Med"},{"key":"hep41083-bib-0023-20240114","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.bcmd.2016.05.004","article-title":"Dietary supplementation with ipriflavone decreases hepatic iron stores in wild type mice","volume":"60","year":"2016","journal-title":"Blood Cells Mol Dis"},{"key":"hep41083-bib-0024-20240114","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1016\/S0893-6080(02)00070-9","article-title":"Analysis and visualization of gene expression data using self\u2010organizing maps","volume":"15","year":"2002","journal-title":"Neural Netw"},{"key":"hep41083-bib-0025-20240114","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/nar\/gkn923","article-title":"Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists","volume":"37","year":"2009","journal-title":"Nucleic Acids Res"},{"key":"hep41083-bib-0026-20240114","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1038\/nprot.2008.211","article-title":"Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources","volume":"4","year":"2009","journal-title":"Nat Protoc"},{"key":"hep41083-bib-0027-20240114","article-title":"Linear models and empirical bayes methods for assessing differential expression in microarray experiments","volume":"3","year":"2004","journal-title":"Stat Appl Genet Mol Biol"},{"key":"hep41083-bib-0028-20240114","doi-asserted-by":"crossref","first-page":"W251","DOI":"10.1093\/nar\/gkv380","article-title":"MetaboAnalyst 3.0\u2010making metabolomics more meaningful","volume":"43","year":"2015","journal-title":"Nucleic Acids Res"},{"key":"hep41083-bib-0029-20240114","doi-asserted-by":"crossref","first-page":"1315","DOI":"10.1002\/hep.26490","article-title":"The small molecule, genistein, increases hepcidin expression in human hepatocytes","volume":"58","year":"2013","journal-title":"Hepatology"},{"key":"hep41083-bib-0030-20240114","doi-asserted-by":"crossref","first-page":"12193","DOI":"10.1073\/pnas.1412631111","article-title":"Modeling host interactions with hepatitis B virus using primary and induced pluripotent stem cell\u2010derived hepatocellular systems","volume":"111","year":"2014","journal-title":"Proc Natl Acad Sci U S A"},{"key":"hep41083-bib-0031-20240114","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/0022-1759(83)90303-4","article-title":"Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays","volume":"65","year":"1983","journal-title":"J Immunol Methods"},{"key":"hep41083-bib-0032-20240114","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1038\/ng1152","article-title":"Regulatory defects in liver and intestine implicate abnormal hepcidin and Cybrd1 expression in mouse hemochromatosis","volume":"34","year":"2003","journal-title":"Nat Genet"},{"key":"hep41083-bib-0033-20240114","doi-asserted-by":"crossref","first-page":"6211","DOI":"10.1007\/s13277-015-3306-5","article-title":"Malic enzyme 1 induces epithelial\u2010mesenchymal transition and indicates poor prognosis in hepatocellular carcinoma","volume":"36","year":"2015","journal-title":"Tumour Biol"},{"key":"hep41083-bib-0034-20240114","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1016\/j.bbabio.2016.01.013","article-title":"Complex I function in mitochondrial supercomplexes","volume":"1857","year":"2016","journal-title":"Biochim Biophys Acta"},{"key":"hep41083-bib-0035-20240114","doi-asserted-by":"crossref","first-page":"e86019","DOI":"10.1371\/journal.pone.0086019","article-title":"Microarray analysis of rat pancreas reveals altered expression of Alox15 and regenerating islet\u2010derived genes in response to iron deficiency and overload","volume":"9","year":"2014","journal-title":"PLoS One"},{"key":"hep41083-bib-0036-20240114","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1002\/jbt.21410","article-title":"Iron overload potentiates diet\u2010induced hypercholesterolemia and reduces liver PPAR\u2010alpha expression in hamsters","volume":"26","year":"2012","journal-title":"J Biochem Mol Toxicol"},{"key":"hep41083-bib-0037-20240114","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1016\/j.biocel.2007.01.021","article-title":"Iron\u2010independent specific protein expression pattern in the liver of HFE\u2010deficient mice","volume":"39","year":"2007","journal-title":"Int J Biochem Cell Biol"},{"key":"hep41083-bib-0038-20240114","doi-asserted-by":"crossref","first-page":"G1490","DOI":"10.1152\/ajpgi.00455.2006","article-title":"Proteomic analysis of hepatic iron overload in mice suggests dysregulation of urea cycle, impairment of fatty acid oxidation, and changes in the methylation cycle","volume":"292","year":"2007","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"hep41083-bib-0039-20240114","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1111\/nyas.13174","article-title":"Deferoxamine ameliorates hepatosteatosis via several mechanisms in ob\/ob mice","volume":"1375","year":"2016","journal-title":"Ann N Y Acad Sci"},{"key":"hep41083-bib-0040-20240114","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1046\/j.1471-4159.2002.00880.x","article-title":"NF\u2010kappaB\u2010mediated up\u2010regulation of Bcl\u2010X(S) and Bax contributes to cytochrome c release in cyanide\u2010induced apoptosis","volume":"81","year":"2002","journal-title":"J Neurochem"},{"key":"hep41083-bib-0041-20240114","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.expneurol.2016.06.008","article-title":"Laquinimod decreases Bax expression and reduces caspase\u20106 activation in neurons","volume":"283","year":"2016","journal-title":"Exp Neurol"},{"key":"hep41083-bib-0042-20240114","doi-asserted-by":"crossref","first-page":"1538","DOI":"10.1080\/15548627.2016.1191723","article-title":"Mir143\u2010BBC3 cascade reduces microglial survival via interplay between apoptosis and autophagy: implications for methamphetamine\u2010mediated neurotoxicity","volume":"12","year":"2016","journal-title":"Autophagy"},{"key":"hep41083-bib-0043-20240114","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1038\/nchembio.1204","article-title":"NNMT promotes epigenetic remodeling in cancer by creating a metabolic methylation sink","volume":"9","year":"2013","journal-title":"Nat Chem Biol"},{"key":"hep41083-bib-0044-20240114","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1038\/nchembio.1234","article-title":"Metabolism: cancer mistunes methylation","volume":"9","year":"2013","journal-title":"Nat Chem Biol"},{"key":"hep41083-bib-0045-20240114","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1086\/430409","article-title":"A genomewide exploration suggests a new candidate gene at chromosome 11q23 as the major determinant of plasma homocysteine levels: results from the GAIT project","volume":"76","year":"2005","journal-title":"Am J Hum Genet"},{"key":"hep41083-bib-0046-20240114","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.thromres.2007.02.012","article-title":"The relation between nicotinamide N\u2010methyltransferase gene polymorphism and plasma homocysteine concentration in healthy Japanese men","volume":"121","year":"2007","journal-title":"Thromb Res"},{"key":"hep41083-bib-0047-20240114","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1089\/gtmb.2013.0309","article-title":"Association of nicotinamide\u2010N\u2010methyltransferase gene rs694539 variant with patients with nonalcoholic steatohepatitis","volume":"17","year":"2013","journal-title":"Genet Test Mol Biomarkers"},{"key":"hep41083-bib-0048-20240114","first-page":"7521942","article-title":"Physiological study on association between nicotinamide N\u2010methyltransferase gene polymorphisms and hyperlipidemia","volume":"2016","year":"2016","journal-title":"Biomed Res Int"},{"key":"hep41083-bib-0049-20240114","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1016\/j.tem.2017.02.004","article-title":"Nicotinamide n\u2010methyltransferase: more than a vitamin B3 clearance enzyme","volume":"28","year":"2017","journal-title":"Trends Endocrinol Metab"}],"container-title":["Hepatology Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fhep4.1083","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/hep4.1083","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/hep4.1083","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/02009842-201710000-00010","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,14]],"date-time":"2024-01-14T17:00:34Z","timestamp":1705251634000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/02009842-201710000-00010"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,9,11]]},"references-count":49,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2017]]}},"URL":"https:\/\/doi.org\/10.1002\/hep4.1083","relation":{},"ISSN":["2471-254X","2471-254X"],"issn-type":[{"value":"2471-254X","type":"print"},{"value":"2471-254X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,9,11]]}}}