{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T23:59:29Z","timestamp":1793923169318,"version":"4.8.0"},"reference-count":68,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,11,9]],"date-time":"2020-11-09T00:00:00Z","timestamp":1604880000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2020,11,9]],"date-time":"2020-11-09T00:00:00Z","timestamp":1604880000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["DK117854"],"award-info":[{"award-number":["DK117854"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Hum Genomics"],"published-print":{"date-parts":[[2020,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Mitochondrial folate enzyme ALDH1L2 (aldehyde dehydrogenase 1 family member L2) converts 10-formyltetrahydrofolate to tetrahydrofolate and CO\n                      <jats:sub>2<\/jats:sub>\n                      simultaneously producing NADPH. We have recently reported that the lack of the enzyme due to compound heterozygous mutations was associated with neuro-ichthyotic syndrome in a male patient. Here, we address the role of ALDH1L2 in cellular metabolism and highlight the mechanism by which the enzyme regulates lipid oxidation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We generated\n                      <jats:italic>Aldh1l2<\/jats:italic>\n                      knockout (KO) mouse model, characterized its phenotype, tissue histology, and levels of reduced folate pools and applied untargeted metabolomics to determine metabolic changes in the liver, pancreas, and plasma caused by the enzyme loss. We have also used NanoString Mouse Inflammation V2 Code Set to analyze inflammatory gene expression and evaluate the role of ALDH1L2 in the regulation of inflammatory pathways.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Both male and female\n                      <jats:italic>Aldh1l2<\/jats:italic>\n                      KO mice were viable and did not show an apparent phenotype. However, H&amp;E and Oil Red O staining revealed the accumulation of lipid vesicles localized between the central veins and portal triads in the liver of\n                      <jats:italic>Aldh1l2<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>-\/-<\/jats:italic>\n                      <\/jats:sup>\n                      male mice indicating abnormal lipid metabolism. The metabolomic analysis showed vastly changed metabotypes in the liver and plasma in these mice suggesting channeling of fatty acids away from \u03b2-oxidation. Specifically, drastically increased plasma acylcarnitine and acylglycine conjugates were indicative of impaired \u03b2-oxidation in the liver. Our metabolomics data further showed that mechanistically, the regulation of lipid metabolism by ALDH1L2 is linked to coenzyme A biosynthesis through the following steps. ALDH1L2 enables sufficient NADPH production in mitochondria to maintain high levels of glutathione, which in turn is required to support high levels of cysteine, the coenzyme A precursor. As the final outcome, the deregulation of lipid metabolism due to ALDH1L2 loss led to decreased ATP levels in mitochondria.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The ALDH1L2 function is important for CoA-dependent pathways including \u03b2-oxidation, TCA cycle, and bile acid biosynthesis. The role of ALDH1L2 in the lipid metabolism explains why the loss of this enzyme is associated with neuro-cutaneous diseases. On a broader scale, our study links folate metabolism to the regulation of lipid homeostasis and the energy balance in the cell.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s40246-020-00291-3","type":"journal-article","created":{"date-parts":[[2020,11,9]],"date-time":"2020-11-09T18:02:36Z","timestamp":1604944956000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Aldh1l2 knockout mouse metabolomics links the loss of the mitochondrial folate enzyme to deregulation of a lipid metabolism observed in rare human disorder"],"prefix":"10.1186","volume":"14","author":[{"given":"Natalia I.","family":"Krupenko","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaspreet","family":"Sharma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Pediaditakis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristi L.","family":"Helke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madeline S.","family":"Hall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuxia","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"Sumner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6926-2776","authenticated-orcid":false,"given":"Sergey A.","family":"Krupenko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,11,9]]},"reference":[{"key":"291_CR1","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1146\/annurev.nutr.012809.104810","volume":"30","author":"AS Tibbetts","year":"2010","unstructured":"Tibbetts AS, Appling DR. Compartmentalization of mammalian folate-mediated one-carbon metabolism. Annu Rev Nutr. 2010;30:57\u201381.","journal-title":"Annu Rev Nutr"},{"issue":"30","key":"291_CR2","doi-asserted-by":"publisher","first-page":"23056","DOI":"10.1074\/jbc.M110.128843","volume":"285","author":"NI Krupenko","year":"2010","unstructured":"Krupenko NI, Dubard ME, Strickland KC, Moxley KM, Oleinik NV, Krupenko SA. ALDH1L2 is the mitochondrial homolog of 10-formyltetrahydrofolate dehydrogenase. J Biol Chem. 2010;285(30):23056\u201363.","journal-title":"J Biol Chem"},{"issue":"7504","key":"291_CR3","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1038\/nature13236","volume":"510","author":"J Fan","year":"2014","unstructured":"Fan J, Ye J, Kamphorst JJ, Shlomi T, Thompson CB, Rabinowitz JD. Quantitative flux analysis reveals folate-dependent NADPH production. Nature. 2014;510(7504):298\u2013302.","journal-title":"Nature"},{"issue":"7577","key":"291_CR4","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1038\/nature15726","volume":"527","author":"E Piskounova","year":"2015","unstructured":"Piskounova E, Agathocleous M, Murphy MM, Hu Z, Huddlestun SE, Zhao Z, Leitch AM, Johnson TM, DeBerardinis RJ, Morrison SJ. Oxidative stress inhibits distant metastasis by human melanoma cells. Nature. 2015;527(7577):186\u201391.","journal-title":"Nature"},{"key":"291_CR5","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1038\/s41525-019-0092-9","volume":"4","author":"C Sarret","year":"2019","unstructured":"Sarret C, Ashkavand Z, Paules E, Dorboz I, Pediaditakis P, Sumner S, Eymard-Pierre E, Francannet C, Krupenko NI, Boespflug-Tanguy O, et al. Deleterious mutations in ALDH1L2 suggest a novel cause for neuro-ichthyotic syndrome. NPJ Genom Med. 2019;4:17.","journal-title":"NPJ Genom Med"},{"issue":"1","key":"291_CR6","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1055\/s-2000-6834","volume":"32","author":"WB Rizzo","year":"2012","unstructured":"Rizzo WB, Jenkens SM, Boucher P. Recognition and diagnosis of neuro-ichthyotic syndromes. Semin Neurol. 2012;32(1):75\u201384.","journal-title":"Semin Neurol"},{"issue":"2","key":"291_CR7","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1002\/humu.23679","volume":"40","author":"M Weustenfeld","year":"2019","unstructured":"Weustenfeld M, Eidelpes R, Schmuth M, Rizzo WB, Zschocke J, Keller MA. Genotype and phenotype variability in Sjogren-Larsson syndrome. Hum Mutat. 2019;40(2):177\u201386.","journal-title":"Hum Mutat"},{"issue":"1-3","key":"291_CR8","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1016\/j.cbi.2008.09.007","volume":"178","author":"SA Krupenko","year":"2009","unstructured":"Krupenko SA. FDH: an aldehyde dehydrogenase fusion enzyme in folate metabolism. Chem Biol Interact. 2009;178(1-3):84\u201393.","journal-title":"Chem Biol Interact"},{"key":"291_CR9","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.cbi.2014.12.022","volume":"234","author":"NI Krupenko","year":"2015","unstructured":"Krupenko NI, Holmes RS, Tsybovsky Y, Krupenko SA. Aldehyde dehydrogenase homologous folate enzymes: evolutionary switch between cytoplasmic and mitochondrial localization. Chem Biol Interact. 2015;234:12\u20137.","journal-title":"Chem Biol Interact"},{"issue":"5","key":"291_CR10","first-page":"227","volume":"13","author":"SA Krupenko","year":"2002","unstructured":"Krupenko SA, Oleinik NV. 10-formyltetrahydrofolate dehydrogenase, one of the major folate enzymes, is down-regulated in tumor tissues and possesses suppressor effects on cancer cells. Cell Growth Differ. 2002;13(5):227\u201336.","journal-title":"Cell Growth Differ"},{"issue":"7","key":"291_CR11","doi-asserted-by":"publisher","first-page":"e0199699","DOI":"10.1371\/journal.pone.0199699","volume":"13","author":"QA Khan","year":"2018","unstructured":"Khan QA, Pediaditakis P, Malakhau Y, Esmaeilniakooshkghazi A, Ashkavand Z, Sereda V, Krupenko NI, Krupenko SA. CHIP E3 ligase mediates proteasomal degradation of the proliferation regulatory protein ALDH1L1 during the transition of NIH3T3 fibroblasts from G0\/G1 to S-phase. PLoS One. 2018;13(7):e0199699.","journal-title":"PLoS One"},{"issue":"1","key":"291_CR12","doi-asserted-by":"publisher","first-page":"14937","DOI":"10.1038\/s41598-019-51397-1","volume":"9","author":"NI Krupenko","year":"2019","unstructured":"Krupenko NI, Sharma J, Pediaditakis P, Fekry B, Helke KL, Du X, Sumner S, Krupenko SA. Cytosolic 10-formyltetrahydrofolate dehydrogenase regulates glycine metabolism in mouse liver. Sci Rep. 2019;9(1):14937.","journal-title":"Sci Rep"},{"key":"291_CR13","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1016\/j.cbi.2019.02.013","volume":"302","author":"SA Krupenko","year":"2019","unstructured":"Krupenko SA, Krupenko NI. Loss of ALDH1L1 folate enzyme confers a selective metabolic advantage for tumor progression. Chem Biol Interact. 2019;302:149\u201355.","journal-title":"Chem Biol Interact"},{"issue":"6","key":"291_CR14","doi-asserted-by":"publisher","first-page":"e5839","DOI":"10.1371\/journal.pone.0005839","volume":"4","author":"DD Anderson","year":"2009","unstructured":"Anderson DD, Stover PJ. SHMT1 and SHMT2 are functionally redundant in nuclear de novo thymidylate biosynthesis. PLoS One. 2009;4(6):e5839.","journal-title":"PLoS One"},{"issue":"2","key":"291_CR15","doi-asserted-by":"publisher","first-page":"256","DOI":"10.1016\/j.bcp.2006.04.005","volume":"72","author":"NV Oleinik","year":"2006","unstructured":"Oleinik NV, Krupenko NI, Reuland SN, Krupenko SA. Leucovorin-induced resistance against FDH growth suppressor effects occurs through DHFR up-regulation. Biochem Pharmacol. 2006;72(2):256\u201366.","journal-title":"Biochem Pharmacol"},{"issue":"38","key":"291_CR16","doi-asserted-by":"publisher","first-page":"26383","DOI":"10.1074\/jbc.M114.569657","volume":"289","author":"NV Oleinik","year":"2014","unstructured":"Oleinik NV, Helke KL, Kistner-Griffin E, Krupenko NI, Krupenko SA. Rho GTPases RhoA and Rac1 mediate effects of dietary folate on metastatic potential of A549 cancer cells through the control of cofilin phosphorylation. J Biol Chem. 2014;289(38):26383\u201394.","journal-title":"J Biol Chem"},{"issue":"9","key":"291_CR17","doi-asserted-by":"publisher","first-page":"889","DOI":"10.1177\/1947601911432495","volume":"2","author":"LA Hoeferlin","year":"2011","unstructured":"Hoeferlin LA, Oleinik NV, Krupenko NI, Krupenko SA. Activation of p21-dependent G1\/G2 arrest in the absence of DNA damage as an antiapoptotic response to metabolic stress. Genes Cancer. 2011;2(9):889\u201399.","journal-title":"Genes Cancer"},{"key":"291_CR18","unstructured":"Evans AM, Bridgewater BR, Liu Q, Mitchell MW, Robinson RJ, Dai H, Stewart SJ, DeHaven CD, Miller LAD. High resolution mass spectrometry improves data quantity and quality as compared to unit mass resolution mass spectrometry in highthroughput profiling metabolomics. Matabolomics. 2014;4(2):1-7."},{"issue":"1","key":"291_CR19","doi-asserted-by":"publisher","DOI":"10.1186\/1758-2946-2-9","volume":"2","author":"CD Dehaven","year":"2010","unstructured":"Dehaven CD, Evans AM, Dai H, Lawton KA. Organization of GC\/MS and LC\/MS metabolomics data into chemical libraries. J Cheminform. 2010;2(1):9.","journal-title":"J Cheminform"},{"issue":"3","key":"291_CR20","doi-asserted-by":"publisher","first-page":"e0150480","DOI":"10.1371\/journal.pone.0150480","volume":"11","author":"O Rafikova","year":"2016","unstructured":"Rafikova O, Meadows ML, Kinchen JM, Mohney RP, Maltepe E, Desai AA, Yuan JX, Garcia JG, Fineman JR, Rafikov R, et al. Metabolic changes precede the development of pulmonary hypertension in the monocrotaline exposed rat lung. PLoS One. 2016;11(3):e0150480.","journal-title":"PLoS One"},{"issue":"4","key":"291_CR21","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1186\/gm332","volume":"4","author":"MV Brown","year":"2012","unstructured":"Brown MV, McDunn JE, Gunst PR, Smith EM, Milburn MV, Troyer DA, Lawton KA. Cancer detection and biopsy classification using concurrent histopathological and metabolomic analysis of core biopsies. Genome Med. 2012;4(4):33.","journal-title":"Genome Med"},{"issue":"1","key":"291_CR22","first-page":"92","volume":"1","author":"B Worley","year":"2013","unstructured":"Worley B, Powers R. Multivariate analysis in metabolomics. Curr Metabolomics. 2013;1(1):92\u2013107.","journal-title":"Curr Metabolomics"},{"key":"291_CR23","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1196\/annals.1427.015","volume":"1147","author":"AA Starkov","year":"2008","unstructured":"Starkov AA. The role of mitochondria in reactive oxygen species metabolism and signaling. Ann N Y Acad Sci. 2008;1147:37\u201352.","journal-title":"Ann N Y Acad Sci"},{"key":"291_CR24","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1016\/j.yjmcc.2014.03.011","volume":"73","author":"A Nickel","year":"2014","unstructured":"Nickel A, Kohlhaas M, Maack C. Mitochondrial reactive oxygen species production and elimination. J Mol Cell Cardiol. 2014;73:26\u201333.","journal-title":"J Mol Cell Cardiol"},{"issue":"2","key":"291_CR25","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1016\/j.mito.2013.01.008","volume":"13","author":"P Venditti","year":"2013","unstructured":"Venditti P, Di Stefano L, Di Meo S. Mitochondrial metabolism of reactive oxygen species. Mitochondrion. 2013;13(2):71\u201382.","journal-title":"Mitochondrion"},{"issue":"1-2","key":"291_CR26","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1016\/j.mam.2008.05.005","volume":"30","author":"SC Lu","year":"2009","unstructured":"Lu SC. Regulation of glutathione synthesis. Mol Aspects Med. 2009;30(1-2):42\u201359.","journal-title":"Mol Aspects Med"},{"issue":"Suppl 2","key":"291_CR27","doi-asserted-by":"publisher","first-page":"S40","DOI":"10.1007\/PL00014300","volume":"157","author":"JD Finkelstein","year":"1998","unstructured":"Finkelstein JD. The metabolism of homocysteine: pathways and regulation. Eur J Pediatr. 1998;157(Suppl 2):S40\u20134.","journal-title":"Eur J Pediatr"},{"issue":"2-3","key":"291_CR28","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1016\/j.plipres.2005.04.001","volume":"44","author":"R Leonardi","year":"2005","unstructured":"Leonardi R, Zhang YM, Rock CO, Jackowski S. Coenzyme A: back in action. Prog Lipid Res. 2005;44(2-3):125\u201353.","journal-title":"Prog Lipid Res"},{"key":"291_CR29","doi-asserted-by":"crossref","unstructured":"Kok DE, O'Flanagan CH, Coleman MF, Ashkavand Z, Hursting SD, Krupenko SA. Effects of folic acid withdrawal on transcriptomic profiles in murine triple-negative breast cancer cell lines. Biochimie. 2020.","DOI":"10.1016\/j.biochi.2020.04.005"},{"issue":"2","key":"291_CR30","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1016\/j.molimm.2012.11.012","volume":"54","author":"AF Kolb","year":"2013","unstructured":"Kolb AF, Petrie L. Folate deficiency enhances the inflammatory response of macrophages. Mol Immunol. 2013;54(2):164\u201372.","journal-title":"Mol Immunol"},{"key":"291_CR31","doi-asserted-by":"crossref","first-page":"4234061","DOI":"10.1155\/2016\/4234061","volume":"2016","author":"S Li","year":"2016","unstructured":"Li S, Hong M, Tan HY, Wang N, Feng Y. Insights into the role and interdependence of oxidative stress and inflammation in liver diseases. Oxid Med Cell Longev. 2016;2016:4234061.","journal-title":"Oxid Med Cell Longev"},{"issue":"15","key":"291_CR32","doi-asserted-by":"publisher","first-page":"3526","DOI":"10.1039\/C8AN00599K","volume":"143","author":"LC Lee","year":"2018","unstructured":"Lee LC, Liong CY, Jemain AA. Partial least squares-discriminant analysis (PLS-DA) for classification of high-dimensional (HD) data: a review of contemporary practice strategies and knowledge gaps. Analyst. 2018;143(15):3526\u201339.","journal-title":"Analyst"},{"issue":"4","key":"291_CR33","doi-asserted-by":"publisher","first-page":"1146","DOI":"10.1039\/C4MB00682H","volume":"11","author":"SY Wang","year":"2015","unstructured":"Wang SY, Wang Y, Jin XW, Zhang Y, Chen JS, Ma WW, Wu YH, Wang DC. A urinary metabolomics study of rats after the exposure to acrylamide by ultra performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry. Mol Biosyst. 2015;11(4):1146\u201355.","journal-title":"Mol Biosyst"},{"key":"291_CR34","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1007\/978-3-319-98788-0_10","volume":"1032","author":"SA Krupenko","year":"2018","unstructured":"Krupenko SA, Krupenko NI. ALDH1L1 and ALDH1L2 folate regulatory enzymes in cancer. Adv Exp Med Biol. 2018;1032:127\u201343.","journal-title":"Adv Exp Med Biol"},{"issue":"2","key":"291_CR35","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1177\/1947601911405841","volume":"2","author":"NV Oleinik","year":"2011","unstructured":"Oleinik NV, Krupenko NI, Krupenko SA. Epigenetic silencing of ALDH1L1, a metabolic regulator of cellular proliferation, in cancers. Genes and Cancer. 2011;2(2):130\u20139.","journal-title":"Genes and Cancer"},{"key":"291_CR36","doi-asserted-by":"crossref","unstructured":"Miyo M, Konno M, Colvin H, Nishida N, Koseki J, Kawamoto K, Tsunekuni K, Nishimura J, Hata T, Takemasa I, et al. The importance of mitochondrial folate enzymes in human colorectal cancer. Oncol Rep. 2016;37(1):417-25.","DOI":"10.3892\/or.2016.5264"},{"key":"291_CR37","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1016\/j.mito.2018.02.009","volume":"46","author":"MM Adeva-Andany","year":"2019","unstructured":"Adeva-Andany MM, Carneiro-Freire N, Seco-Filgueira M, Fernandez-Fernandez C, Mourino-Bayolo D. Mitochondrial beta-oxidation of saturated fatty acids in humans. Mitochondrion. 2019;46:73\u201390.","journal-title":"Mitochondrion"},{"issue":"12","key":"291_CR38","doi-asserted-by":"publisher","first-page":"5044","DOI":"10.1210\/jc.2016-1859","volume":"101","author":"G Xu","year":"2016","unstructured":"Xu G, Hansen JS, Zhao XJ, Chen S, Hoene M, Wang XL, Clemmesen JO, Secher NH, Haring HU, Pedersen BK, et al. Liver and muscle contribute differently to the plasma acylcarnitine pool during fasting and exercise in humans. J Clin Endocrinol Metab. 2016;101(12):5044\u201352.","journal-title":"J Clin Endocrinol Metab"},{"key":"291_CR39","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1186\/s12986-018-0241-7","volume":"15","author":"B Bjorndal","year":"2018","unstructured":"Bjorndal B, Alteras EK, Lindquist C, Svardal A, Skorve J, Berge RK. Associations between fatty acid oxidation, hepatic mitochondrial function, and plasma acylcarnitine levels in mice. Nutr Metab (Lond). 2018;15:10.","journal-title":"Nutr Metab (Lond)"},{"issue":"2","key":"291_CR40","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1038\/s41430-018-0323-7","volume":"73","author":"A Bosy-Westphal","year":"2019","unstructured":"Bosy-Westphal A, Braun W, Albrecht V, Muller MJ. Determinants of ectopic liver fat in metabolic disease. Eur J Clin Nutr. 2019;73(2):209\u201314.","journal-title":"Eur J Clin Nutr"},{"issue":"1","key":"291_CR41","first-page":"1","volume":"8","author":"M Alves-Bezerra","year":"2017","unstructured":"Alves-Bezerra M, Cohen DE. Triglyceride metabolism in the liver. Compr Physiol. 2017;8(1):1\u20138.","journal-title":"Compr Physiol"},{"issue":"9","key":"291_CR42","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1007\/BF03261931","volume":"51","author":"SE Reuter","year":"2012","unstructured":"Reuter SE, Evans AM. Carnitine and acylcarnitines: pharmacokinetic, pharmacological and clinical aspects. Clin Pharmacokinet. 2012;51(9):553\u201372.","journal-title":"Clin Pharmacokinet"},{"issue":"10","key":"291_CR43","doi-asserted-by":"publisher","first-page":"1169","DOI":"10.1096\/fasebj.13.10.1169","volume":"13","author":"SC Lu","year":"1999","unstructured":"Lu SC. Regulation of hepatic glutathione synthesis: current concepts and controversies. FASEB J. 1999;13(10):1169\u201383.","journal-title":"FASEB J"},{"key":"291_CR44","doi-asserted-by":"publisher","first-page":"151","DOI":"10.3389\/fphar.2014.00151","volume":"5","author":"V Ribas","year":"2014","unstructured":"Ribas V, Garcia-Ruiz C, Fernandez-Checa JC. Glutathione and mitochondria. Front Pharmacol. 2014;5:151.","journal-title":"Front Pharmacol"},{"issue":"1","key":"291_CR45","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1111\/j.1742-4658.2006.05607.x","volume":"274","author":"CL Linster","year":"2007","unstructured":"Linster CL, Van Schaftingen E. Vitamin C. Biosynthesis, recycling and degradation in mammals. FEBS J. 2007;274(1):1\u201322.","journal-title":"FEBS J"},{"issue":"5","key":"291_CR46","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1016\/S0940-2993(96)80054-6","volume":"48","author":"M Kretzschmar","year":"1996","unstructured":"Kretzschmar M. Regulation of hepatic glutathione metabolism and its role in hepatotoxicity. Exp Toxicol Pathol. 1996;48(5):439\u201346.","journal-title":"Exp Toxicol Pathol"},{"issue":"3","key":"291_CR47","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1016\/j.clnu.2012.10.008","volume":"32","author":"SA Dello","year":"2013","unstructured":"Dello SA, Neis EP, de Jong MC, van Eijk HM, Kicken CH, Olde Damink SW, Dejong CH. Systematic review of ophthalmate as a novel biomarker of hepatic glutathione depletion. Clin Nutr. 2013;32(3):325\u201330.","journal-title":"Clin Nutr"},{"issue":"6","key":"291_CR48","doi-asserted-by":"publisher","first-page":"877","DOI":"10.1039\/c3ib20245c","volume":"5","author":"S Geenen","year":"2013","unstructured":"Geenen S, Yates JW, Kenna JG, Bois FY, Wilson ID, Westerhoff HV. Multiscale modelling approach combining a kinetic model of glutathione metabolism with PBPK models of paracetamol and the potential glutathione-depletion biomarkers ophthalmic acid and 5-oxoproline in humans and rats. Integr Biol (Camb). 2013;5(6):877\u201388.","journal-title":"Integr Biol (Camb)"},{"key":"291_CR49","doi-asserted-by":"crossref","unstructured":"Rousseau M, Guenard F, Garneau V, Allam-Ndoul B, Lemieux S, Perusse L, Vohl MC. Associations between dietary protein sources, plasma BCAA and short-chain acylcarnitine levels in adults. Nutrients. 2019;11(1):1-16.","DOI":"10.3390\/nu11010173"},{"issue":"9","key":"291_CR50","doi-asserted-by":"publisher","first-page":"1695","DOI":"10.1038\/oby.2009.510","volume":"18","author":"SJ Mihalik","year":"2010","unstructured":"Mihalik SJ, Goodpaster BH, Kelley DE, Chace DH, Vockley J, Toledo FG, DeLany JP. Increased levels of plasma acylcarnitines in obesity and type 2 diabetes and identification of a marker of glucolipotoxicity. Obesity (Silver Spring). 2010;18(9):1695\u2013700.","journal-title":"Obesity (Silver Spring)"},{"issue":"1","key":"291_CR51","doi-asserted-by":"publisher","first-page":"360","DOI":"10.1186\/s13054-018-2275-7","volume":"22","author":"PI Johansson","year":"2018","unstructured":"Johansson PI, Nakahira K, Rogers AJ, McGeachie MJ, Baron RM, Fredenburgh LE, Harrington J, Choi AMK, Christopher KB. Plasma mitochondrial DNA and metabolomic alterations in severe critical illness. Crit Care. 2018;22(1):360.","journal-title":"Crit Care"},{"issue":"6","key":"291_CR52","doi-asserted-by":"publisher","first-page":"985","DOI":"10.1007\/s10545-018-0149-4","volume":"41","author":"A Rossi","year":"2018","unstructured":"Rossi A, Ruoppolo M, Formisano P, Villani G, Albano L, Gallo G, Crisci D, Moccia A, Parenti G, Strisciuglio P, et al. Insulin-resistance in glycogen storage disease type Ia: linking carbohydrates and mitochondria? J Inherit Metab Dis. 2018;41(6):985\u201395.","journal-title":"J Inherit Metab Dis"},{"issue":"3","key":"291_CR53","doi-asserted-by":"publisher","first-page":"404","DOI":"10.1016\/j.metabol.2010.03.006","volume":"60","author":"SC Kalhan","year":"2011","unstructured":"Kalhan SC, Guo L, Edmison J, Dasarathy S, McCullough AJ, Hanson RW, Milburn M. Plasma metabolomic profile in nonalcoholic fatty liver disease. Metabolism. 2011;60(3):404\u201313.","journal-title":"Metabolism"},{"issue":"2","key":"291_CR54","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1007\/s11306-019-1484-7","volume":"15","author":"I Surowiec","year":"2019","unstructured":"Surowiec I, Noordam R, Bennett K, Beekman M, Slagboom PE, Lundstedt T, van Heemst D. Metabolomic and lipidomic assessment of the metabolic syndrome in Dutch middle-aged individuals reveals novel biological signatures separating health and disease. Metabolomics. 2019;15(2):23.","journal-title":"Metabolomics"},{"issue":"9","key":"291_CR55","doi-asserted-by":"publisher","first-page":"1838","DOI":"10.1039\/C7MB00333A","volume":"13","author":"MH Abu Bakar","year":"2017","unstructured":"Abu Bakar MH, Sarmidi MR. Association of cultured myotubes and fasting plasma metabolite profiles with mitochondrial dysfunction in type 2 diabetes subjects. Mol Biosyst. 2017;13(9):1838\u201353.","journal-title":"Mol Biosyst"},{"issue":"6","key":"291_CR56","doi-asserted-by":"publisher","first-page":"1073","DOI":"10.3945\/jn.108.103754","volume":"139","author":"SH Adams","year":"2009","unstructured":"Adams SH, Hoppel CL, Lok KH, Zhao L, Wong SW, Minkler PE, Hwang DH, Newman JW, Garvey WT. Plasma acylcarnitine profiles suggest incomplete long-chain fatty acid beta-oxidation and altered tricarboxylic acid cycle activity in type 2 diabetic African-American women. J Nutr. 2009;139(6):1073\u201381.","journal-title":"J Nutr"},{"key":"291_CR57","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1186\/1758-5996-6-129","volume":"6","author":"JZ Villarreal-Perez","year":"2014","unstructured":"Villarreal-Perez JZ, Villarreal-Martinez JZ, Lavalle-Gonzalez FJ, Torres-Sepulveda Mdel R, Ruiz-Herrera C, Cerda-Flores RM, Castillo-Garcia ER, Rodriguez-Sanchez IP, Martinez de Villarreal LE. Plasma and urine metabolic profiles are reflective of altered beta-oxidation in non-diabetic obese subjects and patients with type 2 diabetes mellitus. Diabetol Metab Syndr. 2014;6:129.","journal-title":"Diabetol Metab Syndr"},{"key":"291_CR58","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1016\/j.diabres.2018.03.058","volume":"140","author":"C Roy","year":"2018","unstructured":"Roy C, Tremblay PY, Anassour-Laouan-Sidi E, Lucas M, Forest JC, Giguere Y, Ayotte P. Risk of gestational diabetes mellitus in relation to plasma concentrations of amino acids and acylcarnitines: a nested case-control study. Diabetes Res Clin Pract. 2018;140:183\u201390.","journal-title":"Diabetes Res Clin Pract"},{"issue":"9","key":"291_CR59","doi-asserted-by":"publisher","first-page":"1138","DOI":"10.1111\/dme.12447","volume":"31","author":"MJ Pena","year":"2014","unstructured":"Pena MJ, Lambers Heerspink HJ, Hellemons ME, Friedrich T, Dallmann G, Lajer M, Bakker SJ, Gansevoort RT, Rossing P, de Zeeuw D, et al. Urine and plasma metabolites predict the development of diabetic nephropathy in individuals with type 2 diabetes mellitus. Diabet Med. 2014;31(9):1138\u201347.","journal-title":"Diabet Med"},{"key":"291_CR60","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1186\/s12014-016-9108-y","volume":"13","author":"MG Jagadeeshaprasad","year":"2016","unstructured":"Jagadeeshaprasad MG, Batkulwar KB, Meshram NN, Tiwari S, Korwar AM, Unnikrishnan AG, Kulkarni MJ. Targeted quantification of N-1-(carboxymethyl) valine and N-1-(carboxyethyl) valine peptides of beta-hemoglobin for better diagnostics in diabetes. Clin Proteomics. 2016;13:7.","journal-title":"Clin Proteomics"},{"issue":"1","key":"291_CR61","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1007\/s12020-012-9760-6","volume":"43","author":"WJ Kim","year":"2013","unstructured":"Kim WJ, Park CY. 1,5-Anhydroglucitol in diabetes mellitus. Endocrine. 2013;43(1):33\u201340.","journal-title":"Endocrine"},{"issue":"15","key":"291_CR62","doi-asserted-by":"publisher","first-page":"1447","DOI":"10.1016\/j.clinbiochem.2013.05.045","volume":"46","author":"Y Zhou","year":"2013","unstructured":"Zhou Y, Qiu L, Xiao Q, Wang Y, Meng X, Xu R, Wang S, Na R. Obesity and diabetes related plasma amino acid alterations. Clin Biochem. 2013;46(15):1447\u201352.","journal-title":"Clin Biochem"},{"issue":"6","key":"291_CR63","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1038\/nri.2017.21","volume":"17","author":"AP West","year":"2017","unstructured":"West AP, Shadel GS. Mitochondrial DNA in innate immune responses and inflammatory pathology. Nat Rev Immunol. 2017;17(6):363\u201375.","journal-title":"Nat Rev Immunol"},{"issue":"3","key":"291_CR64","doi-asserted-by":"publisher","first-page":"272","DOI":"10.1111\/j.1439-0396.2007.00752.x","volume":"92","author":"P Nguyen","year":"2008","unstructured":"Nguyen P, Leray V, Diez M, Serisier S, Le Bloc'h J, Siliart B, Dumon H. Liver lipid metabolism. J Anim Physiol Anim Nutr (Berl). 2008;92(3):272\u201383.","journal-title":"J Anim Physiol Anim Nutr (Berl)"},{"issue":"10","key":"291_CR65","doi-asserted-by":"publisher","first-page":"1141","DOI":"10.1139\/cjpp-2016-0681","volume":"95","author":"V Sid","year":"2017","unstructured":"Sid V, Siow YL. O K: Role of folate in nonalcoholic fatty liver disease. Can J Physiol Pharmacol. 2017;95(10):1141\u20138.","journal-title":"Can J Physiol Pharmacol"},{"issue":"3","key":"291_CR66","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1002\/biof.1154","volume":"40","author":"RP da Silva","year":"2014","unstructured":"da Silva RP, Kelly KB, Al Rajabi A, Jacobs RL. Novel insights on interactions between folate and lipid metabolism. Biofactors. 2014;40(3):277\u201383.","journal-title":"Biofactors"},{"issue":"1","key":"291_CR67","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1007\/s10545-014-9776-6","volume":"38","author":"A Garcia-Cazorla","year":"2015","unstructured":"Garcia-Cazorla A, Mochel F, Lamari F, Saudubray JM. The clinical spectrum of inherited diseases involved in the synthesis and remodeling of complex lipids. A tentative overview. J Inherit Metab Dis. 2015;38(1):19\u201340.","journal-title":"J Inherit Metab Dis"},{"issue":"22","key":"291_CR68","doi-asserted-by":"publisher","first-page":"11676","DOI":"10.1074\/jbc.M116.714030","volume":"291","author":"T Naganuma","year":"2016","unstructured":"Naganuma T, Takagi S, Kanetake T, Kitamura T, Hattori S, Miyakawa T, Sassa T, Kihara A. Disruption of the Sjogren-Larsson syndrome gene Aldh3a2 in mice increases keratinocyte growth and retards skin barrier recovery. J Biol Chem. 2016;291(22):11676\u201388.","journal-title":"J Biol Chem"}],"container-title":["Human Genomics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s40246-020-00291-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/s40246-020-00291-3\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s40246-020-00291-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,17]],"date-time":"2024-08-17T01:06:24Z","timestamp":1723856784000},"score":1,"resource":{"primary":{"URL":"https:\/\/humgenomics.biomedcentral.com\/articles\/10.1186\/s40246-020-00291-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,9]]},"references-count":68,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2020,12]]}},"alternative-id":["291"],"URL":"https:\/\/doi.org\/10.1186\/s40246-020-00291-3","relation":{},"ISSN":["1479-7364"],"issn-type":[{"value":"1479-7364","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,9]]},"assertion":[{"value":"21 September 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 October 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 November 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Not applicable.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no conflicts of interest with the contents of this article.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"41"}}