{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T06:21:11Z","timestamp":1783405271722,"version":"3.54.6"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T00:00:00Z","timestamp":1783382400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Nutr."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Dysregulation of lipid metabolism plays a key role in diabetes mellitus (DM). Phosphatidylethanolamine (PE) and its metabolites, lysophosphatidylethanolamine (LPE) and glycerophosphorylethanolamine (GPE), are involved in cell signaling and mitochondrial homeostasis. Disruption of PE metabolism is associated with insulin sensitivity and mitochondrial dysfunction. However, the mechanism underlying alterations in PE metabolites, especially LPE, in DM remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Six-week-old male C57BL\/6N mice were divided into three groups: control (regular diet,\n                      <jats:italic>n<\/jats:italic>\n                      \u202f=\u202f8), high-fat diet (HFD,\n                      <jats:italic>n<\/jats:italic>\n                      \u202f=\u202f8), and HFD combined with streptozotocin treatment (HFD\/STZ,\n                      <jats:italic>n<\/jats:italic>\n                      \u202f=\u202f6). Lipids were extracted from plasma, kidney, and liver samples using a single-phase method, followed by targeted (LPE 16:0, 18:0, 18:1, 18:2, 20:4, 20:5, and 22:6) and non-targeted liquid chromatography-tandem mass spectrometry. Protein expression was analyzed by Western blotting.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In the plasma of HFD\/STZ mice, the levels of combined LPEs were increased in parallel with PE levels, whereas most LPE species were significantly decreased in the kidneys. Interestingly, GPE levels were markedly increased in the plasma, kidneys, and liver of HFD\/STZ mice. The LPE\/GPE ratio in the plasma and kidney was negatively correlated with key indicators of DM, such as inflammation, glucose intolerance, and renal dysfunction. Furthermore, PNPLA6, a lysophospholipase that cleaves acyl chains from PE and LPE, was upregulated in the kidney of HFD\/STZ mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Upregulation of PNPLA6 was associated with the reduced LPE\/GPE ratio, which may contribute to the progression of DM. This study provides new insights into DM pathology and therapeutic targets.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnut.2026.1799991","type":"journal-article","created":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T05:47:49Z","timestamp":1783403269000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Dysregulation of phosphatidylethanolamine metabolism associated with upregulation of PNPLA6 in high-fat diet\/streptozotocin mice"],"prefix":"10.3389","volume":"13","author":[{"given":"Nao","family":"Inoue","sequence":"first","affiliation":[{"name":"Faculty of Health Sciences, Hokkaido University","place":["Sapporo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsin-Jung","family":"Ho","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences, Hokkaido University","place":["Sapporo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siddabasave Gowda","family":"B. Gowda","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences, Hokkaido University","place":["Sapporo, Japan"]},{"name":"Graduate School of Global Food Resources, Hokkaido University","place":["Sapporo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xun-Zhi","family":"Wu","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences, Hokkaido University","place":["Sapporo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miki","family":"Eguchi","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences, Hokkaido University","place":["Sapporo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minato","family":"Masamura-Takeuchi","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences, Hokkaido University","place":["Sapporo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hitoshi","family":"Chiba","sequence":"additional","affiliation":[{"name":"Department of Nutrition, Sapporo University of Health Sciences","place":["Sapporo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu-Ping","family":"Hui","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences, Hokkaido University","place":["Sapporo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,7]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"1771","DOI":"10.1161\/CIRCRESAHA.115.306884","article-title":"Vascular complications of diabetes","volume":"118","author":"Beckman","year":"2016","journal-title":"Circ Res"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"1497449","DOI":"10.1155\/2021\/1497449","article-title":"Diabetic nephropathy: challenges in pathogenesis, diagnosis, and treatment","volume":"2021","author":"Samsu","year":"2021","journal-title":"Biomed Res Int"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"e39759","DOI":"10.1097\/MD.0000000000039759","article-title":"Prevalence of nephropathy among diabetic patients in north American region: a systematic review and meta-analysis","volume":"103","author":"Zahra","year":"2024","journal-title":"Medicine (Baltimore)"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s101570300000","article-title":"Treatment of diabetic nephropathy with angiotensin II receptor antagonist","volume":"7","author":"Lewis","year":"2003","journal-title":"Clin Exp Nephrol"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"1636","DOI":"10.1373\/clinchem.2007.088260","article-title":"Characterization of diabetic nephropathy by urinary proteomic analysis: identification of a processed ubiquitin form as a differentially excreted protein in diabetic nephropathy patients","volume":"53","author":"Dihazi","year":"2007","journal-title":"Clin Chem"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"483","DOI":"10.3390\/jcm7120483","article-title":"Urinary proteomics for the early diagnosis of diabetic nephropathy in Taiwanese patients","volume":"7","author":"Liao","year":"2018","journal-title":"J Clin Med"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"365","DOI":"10.4062\/biomolther.2020.204","article-title":"Diabetic nephropathy \u2013 a review of risk factors, progression, mechanism, and dietary management","volume":"29","author":"Natesan","year":"2021","journal-title":"Biomol Ther"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"9673","DOI":"10.1038\/s41598-023-36675-3","article-title":"Poor glycemic control and associated factors among patients with type 2 diabetes mellitus: a cross-sectional study","volume":"13","author":"Yahaya","year":"2023","journal-title":"Sci Rep"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1194\/jlr.P040501","article-title":"Altered renal lipid metabolism and renal lipid accumulation in human diabetic nephropathy","volume":"55","author":"Herman-Endelstein","year":"2014","journal-title":"J Lipid Res"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1111\/dom.14007","article-title":"An updated overview of diabetic nephropathy: diagnosis, prognosis, treatment goals and latest guidelines","volume":"22","author":"Selby","year":"2020","journal-title":"Diabetes Obes Metab"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"702","DOI":"10.1111\/jcmm.13984","article-title":"The relationship between phospholipids and insulin resistance: from clinical to experimental studies","volume":"23","author":"Chang","year":"2019","journal-title":"J Cell Mol Med"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/bs.ircmb.2015.10.001","article-title":"Phosphatidylethanolamine metabolism in health and disease","volume":"321","author":"Calzada","year":"2016","journal-title":"Int Rev Cell Mol Biol"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1021\/acsmedchemlett.3c00263","article-title":"Lysophosphatidylcholines enriched with cis and trans palmitoleic acid regulate insulin secretion via GPR119 receptor","volume":"15","author":"Szustak","year":"2024","journal-title":"ACS Med Chem Lett"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"677","DOI":"10.1016\/j.jmb.2012.09.001","article-title":"Phosphatidylethanolamine and cardiolipin differentially affect the stability of mitochondrial respiratory chain supercomplexes","volume":"423","author":"B\u00f6ttinger","year":"2012","journal-title":"J Mol Biol"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1016\/j.jmb.2011.09.023","article-title":"Conservation of lipid functions in cytochrome bc complexes","volume":"414","author":"Hasan","year":"2011","journal-title":"J Mol Biol"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"4158","DOI":"10.1074\/jbc.M112.434183","article-title":"Phosphatidylethanolamine deficiency in mammalian mitochondria impairs oxidative phosphorylation and alters mitochondrial morphology","volume":"288","author":"Tasseva","year":"2013","journal-title":"J Biol Chem"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"100713","DOI":"10.1016\/j.jlr.2024.100713","article-title":"Lysophosphatidylethanolamine improves diastolic dysfunction by alleviating mitochondrial injury in the aging heart","volume":"66","author":"Xu","year":"2025","journal-title":"J Lipid Res"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1016\/j.talanta.2015.10.070","article-title":"Metabolomic profile related to cardiovascular disease in patients with type 2 diabetes mellitus: a pilot study","volume":"148","author":"Garc\u00eda-Fontana","year":"2016","journal-title":"Talanta"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"781417","DOI":"10.3389\/fendo.2021.781417","article-title":"Lipidomics reveals serum specific lipid alterations in diabetic nephropathy","volume":"12","author":"Xu","year":"2021","journal-title":"Front Endocrinol (Lausanne)"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1007\/s11892-019-1263-x","article-title":"Crosstalk between lipids and mitochondria in diabetic kidney disease","volume":"19","author":"Ducasa","year":"2019","journal-title":"Curr Diab Rep"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1089\/ars.2009.2531","article-title":"Mitochondrial dysfunction in diabetes: from molecular mechanisms to functional significance and therapeutic opportunities","volume":"12","author":"Sivitz","year":"2010","journal-title":"Antioxid Redox Signal"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1177\/00045632241280352","article-title":"Determination of plasma lysophosphatidylethanolamines (lyso-PE) by LC-MS\/MS revealed a possible relation between obesity and lyso-PE in Japanese preadolescent children: the Hokkaido study","volume":"62","author":"Inoue","year":"2025","journal-title":"Ann Clin Biochem"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"663","DOI":"10.1016\/s0026-0495(98)90027-0","article-title":"Nongenetic mouse models of non-insulin-dependent diabetes mellitus","volume":"47","author":"Luo","year":"1998","journal-title":"Metabolism"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"e92574","DOI":"10.1371\/journal.pone.0092574","article-title":"Multiple low-dose radiation prevents type 2 diabetes-induced renal damage through attenuation of dyslipidemia and insulin resistance and subsequent renal inflammation and oxidative stress","volume":"9","author":"Shao","year":"2014","journal-title":"PLoS One"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"104746","DOI":"10.1016\/j.phrs.2020.104746","article-title":"Protective effect of ginsenoside Rg5 against kidney injury via inhibition of NLRP3 inflammasome activation and the MAPK signaling pathway in high-fat diet\/streptozotocin-induced diabetic mice","volume":"155","author":"Zhu","year":"2020","journal-title":"Pharmacol Res"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1007\/s00216-020-02996-9","article-title":"Analysis of serum lysophosphatidylethanolamine levels in patients with non\u2013alcoholic fatty liver disease by liquid chromatography-tandem mass spectrometry","volume":"413","author":"Yamamoto","year":"2021","journal-title":"Anal Bioanal Chem"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"2196","DOI":"10.1021\/jasms.1c00138","article-title":"Detection and structural characterization of SFAHFA homologous series in mouse colon contents by LTQ-Orbitrap-MS and their implication in influenza virus infection","volume":"32","author":"Gowda","year":"2021","journal-title":"J Am Soc Mass Spectrom"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"1159","DOI":"10.1038\/s41587-020-0531-2","article-title":"A lipidome atlas in MS-DIAL 4","volume":"38","author":"Tsugawa","year":"2020","journal-title":"Nat Biotechnol"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1210\/er.2006-0035","article-title":"The genetic landscape of type 2 diabetes in mice","volume":"28","author":"Clee","year":"2007","journal-title":"Endocr Rev"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"1077","DOI":"10.2337\/diab.38.9.1077","article-title":"Mesangial expansion as a central mechanism for loss of kidney function in diabetic patients","volume":"38","author":"Steffes","year":"1989","journal-title":"Diabetes"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"9089","DOI":"10.7150\/thno.62724","article-title":"Monoethanolamine-induced glucose deprivation promotes apoptosis through metabolic rewiring in prostate cancer","volume":"11","author":"Garlapati","year":"2021","journal-title":"Theranostics"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1016\/s0006-8993(99)01570-x","article-title":"Phosphatidylcholine and phosphatidylethanolamine metabolites may regulate brain phospholipid catabolism via inhibition of lysophospholipase activity","volume":"834","author":"Fallbrook","year":"1999","journal-title":"Brain Res"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"e4112","DOI":"10.1002\/nbm.4112","article-title":"Focus on the glycerophosphocholine pathway in choline phospholipid metabolism of cancer","volume":"32","author":"Sonkar","year":"2019","journal-title":"NMR Biomed"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"2830","DOI":"10.1073\/pnas.0712245105","article-title":"Discovery of a lysophospholipid acyltransferase family essential for membrane asymmetry and diversity","volume":"105","author":"Hishikawa","year":"2008","journal-title":"Proc Natl Acad Sci USA"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"799","DOI":"10.1194\/jlr.R046094","article-title":"Diversity and function of membrane glycerophospholipids generated by the remodeling pathway in mammalian cells","volume":"55","author":"Hishikawa","year":"2014","journal-title":"J Lipid Res"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"7125","DOI":"10.1007\/s11033-012-1544-9","article-title":"Degradation of mouse NTE-related esterase by macroautophagy and the proteasome","volume":"39","author":"Chang","year":"2012","journal-title":"Mol Biol Rep"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"594","DOI":"10.1016\/j.tem.2021.04.015","article-title":"The ubiquitin-proteasome system and autophagy: self-digestion for metabolic health","volume":"32","author":"Sun-Wang","year":"2021","journal-title":"Trends Endocrinol Metab"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"111940","DOI":"10.1016\/j.celrep.2022.111940","article-title":"Hepatic phosphatidylcholine catabolism driven by PNPLA7 and PNPLA8 supplies endogenous choline to replenish the methionine cycle with methyl groups","volume":"42","author":"Hirabayashi","year":"2023","journal-title":"Cell Rep"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"7983","DOI":"10.1073\/pnas.1232473100","article-title":"Evidence that mouse brain neuropathy target esterase is a lysophospholipase","volume":"100","author":"Quistad","year":"2003","journal-title":"Proc Natl Acad Sci USA"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"19087","DOI":"10.1074\/jbc.M117.792978","article-title":"The phospholipase PNPLA7 functions as a lysophosphatidylcholine hydrolase and interacts with lipid droplets through its catalytic domain","volume":"292","author":"Heier","year":"2017","journal-title":"J Biol Chem"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"2221","DOI":"10.1038\/s41467-025-57402-8","article-title":"PNPLA6 regulates retinal homeostasis by choline through phospholipid turnover","volume":"16","author":"Ono","year":"2025","journal-title":"Nat Commun"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"S63","DOI":"10.1194\/jlr.R800082-JLR200","article-title":"Mammalian patatin domain containing proteins: a family with diverse lipolytic activities involved in multiple biological functions","volume":"50","author":"Kienesberger","year":"2009","journal-title":"J Lipid Res"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"1569","DOI":"10.1002\/hep.31161","article-title":"The patatin-like phospholipase domain containing protein 7 facilitates VLDL secretion by modulating ApoE stability","volume":"72","author":"Wang","year":"2020","journal-title":"Hepatology"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"604","DOI":"10.1038\/s42003-024-06298-z","article-title":"GDE5\/Gpcpd1 activity determines phosphatidylcholine composition in skeletal muscle and regulates contractile force in mice","volume":"7","author":"Aisyah","year":"2024","journal-title":"Commun Biol"},{"key":"ref45","doi-asserted-by":"crossref","DOI":"10.1016\/j.jare.2026.04.018","article-title":"LPCAT3 deficiency drives phospholipid remodeling and mitochondrial oxidative dysfunction to accelerate MASH-HCC development","volume-title":"J Adv Res","author":"Shao","year":"2026"},{"key":"ref46","doi-asserted-by":"publisher","first-page":"677202","DOI":"10.3389\/fendo.2022.677202","article-title":"The changes of lipidomic profiles reveal therapeutic effects of exenatide in patients with type 2 diabetes","volume":"13","author":"Zhang","year":"2022","journal-title":"Front Endocrinol"},{"key":"ref47","doi-asserted-by":"publisher","first-page":"2617","DOI":"10.2337\/dc18-0840","article-title":"Plasma lipidomic profiling and risk of type 2 diabetes in the PREDIMED trial","volume":"41","author":"Razquin","year":"2018","journal-title":"Diabetes Care"},{"key":"ref48","doi-asserted-by":"publisher","first-page":"893","DOI":"10.1007\/s11745-011-3589-2","article-title":"2-polyunsaturated acyl lysophosphatidylethanolamine attenuates inflammatory response in zymosan A-induced peritonitis in mice","volume":"46","author":"Hung","year":"2011","journal-title":"Lipids"},{"key":"ref49","doi-asserted-by":"publisher","first-page":"4865","DOI":"10.3390\/ijms22094865","article-title":"2-arachidonyl-lysophosphatidylethanolamine induces anti-inflammatory effects on macrophages and in carrageenan-induced paw edema","volume":"22","author":"Park","year":"2021","journal-title":"Int J Mol Sci"},{"key":"ref50","doi-asserted-by":"publisher","first-page":"457","DOI":"10.3390\/metabo14080457","article-title":"Alterations in choline metabolism in non-obese individuals with insulin resistance and type 2 diabetes mellitus","volume":"14","author":"Al-Sulaiti","year":"2024","journal-title":"Meta"},{"key":"ref51","doi-asserted-by":"publisher","first-page":"348","DOI":"10.1186\/s12967-019-2096-8","article-title":"Metabolic signature of obesity-associated insulin resistance and type 2 diabetes","volume":"17","author":"Al-Sulaiti","year":"2019","journal-title":"J Transl Med"}],"container-title":["Frontiers in Nutrition"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnut.2026.1799991\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T05:47:50Z","timestamp":1783403270000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnut.2026.1799991\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,7]]},"references-count":51,"alternative-id":["10.3389\/fnut.2026.1799991"],"URL":"https:\/\/doi.org\/10.3389\/fnut.2026.1799991","relation":{},"ISSN":["2296-861X"],"issn-type":[{"value":"2296-861X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,7]]},"article-number":"1799991"}}