{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T17:46:26Z","timestamp":1785433586939,"version":"3.56.0"},"posted":{"date-parts":[[2025,10,17]]},"group-title":"Physiology","reference-count":62,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T00:00:00Z","timestamp":1760659200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"id":[{"id":"https:\/\/ror.org\/00k86s890","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,12,23]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Dietary sulfur amino acid restriction (SAAR) improves whole-body glucose homeostasis, elevates liver insulin action, and lowers liver triglycerides. These adaptations are associated with an increased expression of hepatic\n                  <jats:italic>de novo<\/jats:italic>\n                  serine synthesis enzymes, phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase 1 (PSAT1). This study tested the hypothesis that enhanced hepatic serine synthesis is necessary for glucose and lipid adaptations to SAAR. Hepatocyte-specific PSAT1 knockout (KO) mice and wild type (WT) littermates were fed a high-fat control or SAAR diet. In WT mice, SAAR increased liver PSAT1 protein (\u223c70-fold), serine concentration (\u223c2-fold), and\n                  <jats:sup>13<\/jats:sup>\n                  C-serine (\u223c20-fold) following an intravenous infusion of [U-\n                  <jats:sup>13<\/jats:sup>\n                  C]glucose. The elevated liver serine and partitioning of circulating glucose to liver serine by SAAR were attenuated in KO mice. This was accompanied by a blunted improvement in glucose tolerance in KO mice fed a SAAR diet. Interestingly, SAAR decreased liver lysine lactoylation, a SAA-supported post-translational modification known to inhibit PHGDH enzymatic activity. This suggests dietary SAAR may increase serine synthesis, in part, by lowering lysine lactoylation. Beyond glucose metabolism, dietary SAAR reduced body weight, adiposity, and liver triglycerides similarly in WT and KO mice. Collectively, these results demonstrate that hepatic PSAT1 is necessary for glucose, but not lipid, adaptations to SAAR.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Graphical Abstract<\/jats:title>\n                  <jats:p>Schematic representation of liver glucose adaptations to SAAR<\/jats:p>\n                  <jats:fig id=\"ufig1\" position=\"float\" fig-type=\"figure\" orientation=\"portrait\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"682938v2_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.1101\/2025.10.16.682938","type":"posted-content","created":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T22:30:14Z","timestamp":1760740214000},"source":"Crossref","is-referenced-by-count":0,"title":["Dietary sulfur amino acid restriction improves glucose homeostasis through hepatic\n                  <i>de novo<\/i>\n                  serine synthesis"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5634-924X","authenticated-orcid":false,"given":"Andres F.","family":"Ortega","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-8408-3965","authenticated-orcid":false,"given":"Cha Mee","family":"Vang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ferrol I.","family":"Rome","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaitlyn M.","family":"Andreoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aiden M.","family":"Phoebe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7685-1803","authenticated-orcid":false,"given":"Alisa B.","family":"Nelson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8597-4426","authenticated-orcid":false,"given":"Peter A.","family":"Crawford","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5612-0680","authenticated-orcid":false,"given":"James J.","family":"Galligan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6557-3737","authenticated-orcid":false,"given":"Stanley Ching-Cheng","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2674-7359","authenticated-orcid":false,"given":"Curtis C.","family":"Hughey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025122608100467000_2025.10.16.682938v2.1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-nutr-062320-111849"},{"key":"2025122608100467000_2025.10.16.682938v2.2","doi-asserted-by":"publisher","DOI":"10.1002\/oby.21806"},{"key":"2025122608100467000_2025.10.16.682938v2.3","doi-asserted-by":"publisher","DOI":"10.1111\/j.1474-9726.2006.00220.x"},{"issue":"1","key":"2025122608100467000_2025.10.16.682938v2.4","doi-asserted-by":"crossref","first-page":"5073","DOI":"10.1038\/s41598-022-08978-4","article-title":"Metabolic benefits of methionine restriction in adult mice do not require functional methionine sulfoxide reductase A (MsrA)","volume":"12","year":"2022","journal-title":"Sci Rep"},{"key":"2025122608100467000_2025.10.16.682938v2.5","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-10381-3"},{"key":"2025122608100467000_2025.10.16.682938v2.6","doi-asserted-by":"publisher","DOI":"10.1111\/acel.12238"},{"key":"2025122608100467000_2025.10.16.682938v2.7","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0051357"},{"key":"2025122608100467000_2025.10.16.682938v2.8","doi-asserted-by":"publisher","DOI":"10.1096\/fj.14-270348"},{"key":"2025122608100467000_2025.10.16.682938v2.9","doi-asserted-by":"publisher","DOI":"10.2337\/db16-1212"},{"key":"2025122608100467000_2025.10.16.682938v2.10","doi-asserted-by":"publisher","DOI":"10.2337\/db15-1324"},{"key":"2025122608100467000_2025.10.16.682938v2.11","doi-asserted-by":"publisher","DOI":"10.2337\/db14-0464"},{"key":"2025122608100467000_2025.10.16.682938v2.12","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2010-2493"},{"issue":"1","key":"2025122608100467000_2025.10.16.682938v2.13","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1186\/s12967-023-04833-w","article-title":"Dietary sulfur amino acid restriction in humans with overweight and obesity: a translational randomized controlled trial","volume":"22","year":"2024","journal-title":"J Transl Med"},{"issue":"2","key":"2025122608100467000_2025.10.16.682938v2.14","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1007\/s12603-023-1883-3","article-title":"Dietary Methionine and Total Sulfur Amino Acid Restriction in Healthy Adults","volume":"27","year":"2023","journal-title":"J Nutr Health Aging"},{"key":"2025122608100467000_2025.10.16.682938v2.15","doi-asserted-by":"publisher","DOI":"10.3390\/nu13082665"},{"key":"2025122608100467000_2025.10.16.682938v2.16","first-page":"6","article-title":"Hepatic Nfe2l2 Is Not an Essential Mediator of the Metabolic Phenotype Produced by Dietary Methionine Restriction","volume":"13","year":"2021","journal-title":"Nutrients"},{"issue":"5","key":"2025122608100467000_2025.10.16.682938v2.17","doi-asserted-by":"crossref","first-page":"102470","DOI":"10.1016\/j.isci.2021.102470","article-title":"Implementation of dietary methionine restriction using casein after selective, oxidative deletion of methionine","volume":"24","year":"2021","journal-title":"iScience"},{"key":"2025122608100467000_2025.10.16.682938v2.18","doi-asserted-by":"crossref","unstructured":"Stone, K.P. , Ghosh, S. , Kovalik, J.P. , Orgeron, M. , Wanders, D. , Sims, L.C. , et al., 2021. The acute transcriptional responses to dietary methionine restriction are triggered by inhibition of ternary complex formation and linked to Erk1\/2, mTOR, and ATF 4. Sci Rep 11(1):3765.","DOI":"10.1038\/s41598-021-83380-0"},{"key":"2025122608100467000_2025.10.16.682938v2.19","doi-asserted-by":"publisher","DOI":"10.1002\/oby.22919"},{"key":"2025122608100467000_2025.10.16.682938v2.20","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0177513"},{"key":"2025122608100467000_2025.10.16.682938v2.21","doi-asserted-by":"crossref","first-page":"101452","DOI":"10.1016\/j.molmet.2022.101452","article-title":"Disrupted liver oxidative metabolism in glycine N-methyltransferase-deficient mice is mitigated by dietary methionine restriction","volume":"58","year":"2022","journal-title":"Mol Metab"},{"issue":"4","key":"2025122608100467000_2025.10.16.682938v2.22","first-page":"960","article-title":"Pharmacological recapitulation of the lean phenotype induced by the lifespan-extending sulfur amino acid-restricted diet","volume":"17","year":"2025","journal-title":"Aging (Albany NY"},{"issue":"12","key":"2025122608100467000_2025.10.16.682938v2.23","doi-asserted-by":"crossref","first-page":"e13739","DOI":"10.1111\/acel.13739","article-title":"Cysteine restriction-specific effects of sulfur amino acid restriction on lipid metabolism","volume":"21","year":"2022","journal-title":"Aging Cell"},{"key":"2025122608100467000_2025.10.16.682938v2.24","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.R112.357194"},{"key":"2025122608100467000_2025.10.16.682938v2.25","doi-asserted-by":"publisher","DOI":"10.3390\/nu13020583"},{"key":"2025122608100467000_2025.10.16.682938v2.26","doi-asserted-by":"publisher","DOI":"10.2337\/db14-1368"},{"key":"2025122608100467000_2025.10.16.682938v2.27","doi-asserted-by":"publisher","DOI":"10.1016\/j.metabol.2019.154000"},{"key":"2025122608100467000_2025.10.16.682938v2.28","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-022-01145-x"},{"key":"2025122608100467000_2025.10.16.682938v2.29","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00222.2022"},{"key":"2025122608100467000_2025.10.16.682938v2.30","doi-asserted-by":"publisher","DOI":"10.1016\/0003-2697(76)90014-2"},{"key":"2025122608100467000_2025.10.16.682938v2.31","doi-asserted-by":"crossref","unstructured":"Puchalska, P. , Crawford, P.A ., 2019. Application of stable isotope labels for metabolomics in studies in fatty liver disease. Metabolomics: Methods and Protocols. Springer, p. 259\u2013272.","DOI":"10.1007\/978-1-4939-9488-5_20"},{"issue":"5","key":"2025122608100467000_2025.10.16.682938v2.32","doi-asserted-by":"crossref","first-page":"1976","DOI":"10.3390\/ijms26051976","article-title":"Deciphering Colorectal Cancer\u2013Hepatocyte Interactions: A Multiomics Platform for Interrogation of Metabolic Crosstalk in the Liver\u2013Tumor Microenvironment","volume":"26","year":"2025","journal-title":"International journal of molecular sciences"},{"key":"2025122608100467000_2025.10.16.682938v2.33","doi-asserted-by":"publisher","DOI":"10.1126\/SCIADV.ADS7321"},{"key":"2025122608100467000_2025.10.16.682938v2.34","doi-asserted-by":"publisher","DOI":"10.1007\/s13361-017-1608-0"},{"issue":"2","key":"2025122608100467000_2025.10.16.682938v2.35","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/j.chembiol.2019.11.005","article-title":"Non-enzymatic Lysine Lactoylation of Glycolytic Enzymes","volume":"27","year":"2020","journal-title":"Cell Chem Biol"},{"key":"2025122608100467000_2025.10.16.682938v2.36","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1802901115"},{"key":"2025122608100467000_2025.10.16.682938v2.37","doi-asserted-by":"publisher","DOI":"10.1021\/acs.analchem.6b04105"},{"key":"2025122608100467000_2025.10.16.682938v2.38","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2012.10.019"},{"issue":"9","key":"2025122608100467000_2025.10.16.682938v2.39","doi-asserted-by":"crossref","first-page":"1727","DOI":"10.1210\/js.2019-00065","article-title":"Hyperinsulinemia: An Early Indicator of Metabolic Dysfunction","volume":"3","year":"2019","journal-title":"J Endocr Soc"},{"issue":"3","key":"2025122608100467000_2025.10.16.682938v2.40","first-page":"e211263","article-title":"Temporal Associations Among Body Mass Index","volume":"4","year":"2021","journal-title":"Fasting Insulin, and Systemic Inflammation: A Systematic Review and Meta-analysis. JAMA Network Open"},{"key":"2025122608100467000_2025.10.16.682938v2.41","first-page":"5","article-title":"The Role of the Transsulfuration Pathway in Non-Alcoholic Fatty Liver Disease","volume":"10","year":"2021","journal-title":"J Clin Med"},{"issue":"7","key":"2025122608100467000_2025.10.16.682938v2.42","doi-asserted-by":"crossref","first-page":"e202401086","DOI":"10.1002\/cbic.202401086","article-title":"Glyoxalase 2 Coordinates de Novo Serine Metabolism","volume":"26","year":"2025","journal-title":"Chembiochem"},{"key":"2025122608100467000_2025.10.16.682938v2.43","doi-asserted-by":"publisher","DOI":"10.1016\/j.copbio.2015.02.003"},{"issue":"3","key":"2025122608100467000_2025.10.16.682938v2.44","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1016\/j.celrep.2016.09.042","article-title":"Breast cancer-derived lung metastases show increased pyruvate carboxylase-dependent anaplerosis","volume":"17","year":"2016","journal-title":"Cell reports"},{"key":"2025122608100467000_2025.10.16.682938v2.45","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.R117.776054"},{"issue":"4","key":"2025122608100467000_2025.10.16.682938v2.46","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1016\/j.medj.2021.01.002","article-title":"Isotope tracing reveals glycolysis and oxidative metabolism in childhood tumors of multiple histologies","volume":"2","year":"2021","journal-title":"Med"},{"key":"2025122608100467000_2025.10.16.682938v2.47","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.56782"},{"key":"2025122608100467000_2025.10.16.682938v2.48","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abq5206"},{"issue":"3","key":"2025122608100467000_2025.10.16.682938v2.49","doi-asserted-by":"crossref","first-page":"e0194414","DOI":"10.1371\/journal.pone.0194414","article-title":"L-serine supplementation lowers diabetes incidence and improves blood glucose homeostasis in NOD mice","volume":"13","year":"2018","journal-title":"PLoS ONE"},{"key":"2025122608100467000_2025.10.16.682938v2.50","first-page":"9","article-title":"L-Serine Supplementation Blunts Fasting-Induced Weight Regain by Increasing Brown Fat Thermogenesis","volume":"14","year":"2022","journal-title":"Nutrients"},{"key":"2025122608100467000_2025.10.16.682938v2.51","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-nutr-061021-022648"},{"key":"2025122608100467000_2025.10.16.682938v2.52","doi-asserted-by":"publisher","DOI":"10.1042\/bj3440015"},{"issue":"8","key":"2025122608100467000_2025.10.16.682938v2.53","doi-asserted-by":"crossref","first-page":"1693","DOI":"10.1093\/jn\/122.8.1693","article-title":"The splanchnic organs, liver and kidney have unique roles in the metabolism of sulfur amino acids and their metabolites in rats","volume":"122","year":"1992","journal-title":"J Nutr"},{"issue":"3","key":"2025122608100467000_2025.10.16.682938v2.54","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1093\/jn\/122.3.420","article-title":"Cysteine concentration regulates cysteine metabolism to glutathione, sulfate and taurine in rat hepatocytes","volume":"122","year":"1992","journal-title":"J Nutr"},{"issue":"9","key":"2025122608100467000_2025.10.16.682938v2.55","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.1093\/jn\/121.9.1341","article-title":"Uptake and metabolism of L-2-oxo-[35S]thiazolidine-4-carboxylate by rat cells is slower than that of L-[35S]cysteine or L-[35S]methionine","volume":"121","year":"1991","journal-title":"J Nutr"},{"issue":"4","key":"2025122608100467000_2025.10.16.682938v2.56","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1093\/jn\/125.4.933","article-title":"Rats fed a low protein diet supplemented with sulfur amino acids have increased cysteine dioxygenase activity and increased taurine production in hepatocytes","volume":"125","year":"1995","journal-title":"J Nutr"},{"key":"2025122608100467000_2025.10.16.682938v2.57","doi-asserted-by":"crossref","unstructured":"Farrera, D.O. , Galligan, J.J ., 2022. The Human Glyoxalase Gene Family in Health and Disease. Chem Res Toxicol.","DOI":"10.1021\/acs.chemrestox.2c00182"},{"key":"2025122608100467000_2025.10.16.682938v2.58","doi-asserted-by":"crossref","unstructured":"Trujillo, M.N. , Jennings, E.Q. , Hoffman, E.A. , Zhang, H. , Phoebe, A.M. , Mastin, G.E. , et al., 2024. Lactoylglutathione promotes inflammatory signaling in macrophages through histone lactoylation. Mol Metab:101888.","DOI":"10.1016\/j.molmet.2024.101888"},{"key":"2025122608100467000_2025.10.16.682938v2.59","first-page":"3","article-title":"Dietary sulfur amino acid restriction improves metabolic health by reducing fat mass","volume":"4","year":"2025","journal-title":"Life Metab"},{"key":"2025122608100467000_2025.10.16.682938v2.60","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms11457"},{"key":"2025122608100467000_2025.10.16.682938v2.61","doi-asserted-by":"publisher","DOI":"10.2337\/db13-0501"},{"issue":"9","key":"2025122608100467000_2025.10.16.682938v2.62","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.1517\/17425255.2013.796929","article-title":"Glycine conjugation: importance in metabolism, the role of glycine N-acyltransferase, and factors that influence interindividual variation","volume":"9","year":"2013","journal-title":"Expert opinion on drug metabolism & toxicology"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.10.16.682938","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T05:07:01Z","timestamp":1782277621000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.10.16.682938"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,17]]},"references-count":62,"URL":"https:\/\/doi.org\/10.1101\/2025.10.16.682938","relation":{"is-preprint-of":[{"id-type":"doi","id":"10.1016\/j.molmet.2026.102325","asserted-by":"subject"}]},"subject":[],"published":{"date-parts":[[2025,10,17]]},"subtype":"preprint"}}