{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T21:13:14Z","timestamp":1772572394310,"version":"3.50.1"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2015,7,1]],"date-time":"2015-07-01T00:00:00Z","timestamp":1435708800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2015,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Lymphangioleiomyomatosis (LAM) is a destructive lung disease affecting women. LAM is caused by mutations in the tuberous sclerosis complex (TSC) genes. The TSC protein complex inhibits the mechanistic\/mammalian target of rapamycin complex 1 (mTORC1), which is a master regulator of cellular metabolism. Using mass spectrometry\u2013based lipid profiling, we analyzed plasma from patients with LAM and discovered elevated levels of four lysophosphatidylcholine (LPC) species (C16:0, C18:0, C18:1, and C20:4) compared with those in healthy control women. To investigate whether these lipids are generated in a TSC2-dependent manner, we profiled in vitro preclinical models of TSC\/LAM and found significant LPC accumulation in TSC2-deficient cells relative to TSC2-expressing control cells. These lysoglycerophospholipid changes occurred alongside changes in other phospholipid and neutral lipid species. Treatment with rapamycin or torin1 or down-regulation of sterol regulatory element-binding protein (SREBP), a lipogenic transcription factor, did not suppress LPC in TSC2-deficient cells. Inhibition of distinct isoforms of phospholipase A2 decreased the proliferation of TSC2-deficient cells. Collectively, these results demonstrate that TSC2-deficient cells have enhanced choline phospholipid metabolism and reveal a novel function of the TSC proteins in choline lysoglycerophospholipid metabolism, with implications for disease pathogenesis and targeted therapeutic strategies.<\/jats:p>","DOI":"10.1165\/rcmb.2014-0379rc","type":"journal-article","created":{"date-parts":[[2015,3,17]],"date-time":"2015-03-17T18:15:23Z","timestamp":1426616123000},"page":"33-41","source":"Crossref","is-referenced-by-count":34,"title":["Tuberous Sclerosis Complex 2 Loss Increases Lysophosphatidylcholine Synthesis in Lymphangioleiomyomatosis"],"prefix":"10.1093","volume":"53","author":[{"given":"Carmen","family":"Priolo","sequence":"first","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"St\u00e9phane J. H.","family":"Ricoult","sequence":"additional","affiliation":[{"name":"Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, Massachusetts; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Damir","family":"Khabibullin","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Harilaos","family":"Filippakis","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jane","family":"Yu","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brendan D.","family":"Manning","sequence":"additional","affiliation":[{"name":"Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, Massachusetts; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Clary","family":"Clish","sequence":"additional","affiliation":[{"name":"Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth P.","family":"Henske","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2015,7,1]]},"reference":[{"key":"2026021122330967700_bib1","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1056\/NEJMra055323","article-title":"The tuberous sclerosis complex","volume":"355","author":"Crino","year":"2006","journal-title":"N Engl J Med"},{"key":"2026021122330967700_bib2","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1378\/chest.12-2813","article-title":"Lymphangioleiomyomatosis screening in women with tuberous sclerosis","volume":"144","author":"Cudzilo","year":"2013","journal-title":"Chest"},{"key":"2026021122330967700_bib3","doi-asserted-by":"crossref","first-page":"30958","DOI":"10.1074\/jbc.M202678200","article-title":"Tuberin regulates p70 S6 kinase activation and ribosomal protein S6 phosphorylation: a role for the TSC2 tumor suppressor gene in pulmonary lymphangioleiomyomatosis (LAM)","volume":"277","author":"Goncharova","year":"2002","journal-title":"J Biol Chem"},{"key":"2026021122330967700_bib4","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1016\/S0960-9822(03)00506-2","article-title":"Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb","volume":"13","author":"Tee","year":"2003","journal-title":"Curr Biol"},{"key":"2026021122330967700_bib5","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/j.cell.2005.10.024","article-title":"mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events","volume":"123","author":"Holz","year":"2005","journal-title":"Cell"},{"key":"2026021122330967700_bib6","doi-asserted-by":"crossref","first-page":"1981","DOI":"10.1091\/mbc.e08-12-1248","article-title":"Nutrient-dependent mTORC1 association with the ULK1\u2013Atg13\u2013FIP200 complex required for autophagy","volume":"20","author":"Hosokawa","year":"2009","journal-title":"Mol Biol Cell"},{"key":"2026021122330967700_bib7","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1016\/j.cell.2013.04.023","article-title":"The mTORC1 pathway stimulates glutamine metabolism and cell proliferation by repressing SIRT4","volume":"153","author":"Csibi","year":"2013","journal-title":"Cell"},{"key":"2026021122330967700_bib8","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.molcel.2010.06.022","article-title":"Activation of a metabolic gene regulatory network downstream of mTOR complex 1","volume":"39","author":"Duvel","year":"2010","journal-title":"Mol Cell"},{"key":"2026021122330967700_bib9","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1016\/j.molcel.2010.05.007","article-title":"Glucose addiction of TSC null cells is caused by failed mTORC1-dependent balancing of metabolic demand with supply","volume":"38","author":"Choo","year":"2010","journal-title":"Mol Cell"},{"key":"2026021122330967700_bib10","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1158\/1541-7786.MCR-13-0258-T","article-title":"Autophagy-dependent metabolic reprogramming sensitizes TSC2-deficient cells to the antimetabolite 6-aminonicotinamide","volume":"12","author":"Parkhitko","year":"2014","journal-title":"Mol Cancer Res"},{"key":"2026021122330967700_bib11","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1126\/science.1228792","article-title":"Stimulation of de novo pyrimidine synthesis by growth signaling through mTOR and S6K1","volume":"339","author":"Ben-Sahra","year":"2013","journal-title":"Science"},{"key":"2026021122330967700_bib12","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1016\/j.cell.2011.06.034","article-title":"mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway","volume":"146","author":"Peterson","year":"2011","journal-title":"Cell"},{"key":"2026021122330967700_bib13","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.1194\/jlr.M100417-JLR200","article-title":"Transcriptional activities of nuclear SREBP-1a, -1c, and -2 to different target promoters of lipogenic and cholesterogenic genes","volume":"43","author":"Amemiya-Kudo","year":"2002","journal-title":"J Lipid Res"},{"key":"2026021122330967700_bib14","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1038\/nrc3379","article-title":"Phospholipase signalling networks in cancer","volume":"12","author":"Park","year":"2012","journal-title":"Nat Rev Cancer"},{"key":"2026021122330967700_bib15","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.surg.2012.05.043","article-title":"Increased phospholipase A2 and lyso-phosphatidylcholine levels are associated with surfactant dysfunction in lung contusion injury in mice","volume":"153","author":"Machado-Aranda","year":"2013","journal-title":"Surgery"},{"key":"2026021122330967700_bib16","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.18632\/oncotarget.397","article-title":"Phospholipase PLA2G7, associated with aggressive prostate cancer, promotes prostate cancer cell migration and invasion and is inhibited by statins","volume":"2","author":"Vainio","year":"2011","journal-title":"Oncotarget"},{"key":"2026021122330967700_bib17","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1016\/S0002-9440(10)65747-1","article-title":"Potential angiogenic role of platelet-activating factor in human breast cancer","volume":"153","author":"Montrucchio","year":"1998","journal-title":"Am J Pathol"},{"key":"2026021122330967700_bib18","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.bbalip.2012.07.019","article-title":"Lysoglycerophospholipids in chronic inflammatory disorders: the PLA(2)\/LPC and ATX\/LPA axes","volume":"1831","author":"Sevastou","year":"2013","journal-title":"Biochim Biophys Acta"},{"key":"2026021122330967700_bib19","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.2174\/1381612053507521","article-title":"Phospholipase A2 inhibitors as potential anti-inflammatory agents","volume":"11","author":"Meyer","year":"2005","journal-title":"Curr Pharm Des"},{"key":"2026021122330967700_bib20","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/j.cmet.2014.05.019","article-title":"Lysophospholipid acyltransferases mediate phosphatidylcholine diversification to achieve the physical properties required in vivo","volume":"20","author":"Harayama","year":"2014","journal-title":"Cell Metab"},{"key":"2026021122330967700_bib21","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1016\/j.cmet.2013.10.002","article-title":"LXRs regulate ER stress and inflammation through dynamic modulation of membrane phospholipid composition","volume":"18","author":"Rong","year":"2013","journal-title":"Cell Metab"},{"key":"2026021122330967700_bib22","first-page":"1568","article-title":"Rodent model of reproductive tract leiomyomata: establishment and characterization of tumor-derived cell lines","volume":"146","author":"Howe","year":"1995","journal-title":"Am J Pathol"},{"key":"2026021122330967700_bib23","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1016\/j.cmet.2008.07.007","article-title":"SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth","volume":"8","author":"Porstmann","year":"2008","journal-title":"Cell Metab"},{"key":"2026021122330967700_bib24","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1172\/JCI0215593","article-title":"SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver","volume":"109","author":"Horton","year":"2002","journal-title":"J Clin Invest"},{"key":"2026021122330967700_bib25","doi-asserted-by":"crossref","first-page":"8023","DOI":"10.1074\/jbc.M900301200","article-title":"An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1","volume":"284","author":"Thoreen","year":"2009","journal-title":"J Biol Chem"},{"key":"2026021122330967700_bib26","doi-asserted-by":"crossref","first-page":"6085","DOI":"10.1073\/pnas.97.11.6085","article-title":"Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis","volume":"97","author":"Carsillo","year":"2000","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026021122330967700_bib27","doi-asserted-by":"crossref","first-page":"1537","DOI":"10.1164\/ajrccm.164.8.2104095","article-title":"Chromosome 16 loss of heterozygosity in tuberous sclerosis and sporadic lymphangiomyomatosis","volume":"164","author":"Yu","year":"2001","journal-title":"Am J Respir Crit Care Med"},{"key":"2026021122330967700_bib28","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1164\/ajrccm.187.6.663","article-title":"Exonic mutations of TSC2\/TSC1 are common but not seen in all sporadic pulmonary lymphangioleiomyomatosis","volume":"187","author":"Badri","year":"2013","journal-title":"Am J Respir Crit Care Med"},{"key":"2026021122330967700_bib29","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/1476-511X-6-17","article-title":"Plasma lyso-phosphatidylcholine concentration is decreased in cancer patients with weight loss and activated inflammatory status","volume":"6","author":"Taylor","year":"2007","journal-title":"Lipids Health Dis"},{"key":"2026021122330967700_bib30","doi-asserted-by":"crossref","first-page":"1657","DOI":"10.1373\/clinchem.2012.199133","article-title":"Reproducibility of metabolomic profiles among men and women in 2 large cohort studies","volume":"59","author":"Townsend","year":"2013","journal-title":"Clin Chem"},{"key":"2026021122330967700_bib31","doi-asserted-by":"crossref","first-page":"2696","DOI":"10.1200\/JCO.2006.08.5571","article-title":"Plasma lysophosphatidylcholine levels: potential biomarkers for colorectal cancer","volume":"25","author":"Zhao","year":"2007","journal-title":"J Clin Oncol"},{"key":"2026021122330967700_bib32","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1056\/NEJMc0707517","article-title":"Diagnostic potential of serum VEGF-D for lymphangioleiomyomatosis","volume":"358","author":"Young","year":"2008","journal-title":"N Engl J Med"},{"key":"2026021122330967700_bib33","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1089\/lrb.2006.4.143","article-title":"Vascular endothelial growth factor-D is increased in serum of patients with lymphangioleiomyomatosis","volume":"4","author":"Seyama","year":"2006","journal-title":"Lymphat Res Biol"},{"key":"2026021122330967700_bib34","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1378\/chest.10-0573","article-title":"Serum vascular endothelial growth factor-D prospectively distinguishes lymphangioleiomyomatosis from other diseases","volume":"138","author":"Young","year":"2010","journal-title":"Chest"},{"key":"2026021122330967700_bib35","doi-asserted-by":"crossref","first-page":"1398","DOI":"10.1093\/jnci\/djq290","article-title":"Cytosolic phospholipase A2 and lysophospholipids in tumor angiogenesis","volume":"102","author":"Linkous","year":"2010","journal-title":"J Natl Cancer Inst"},{"key":"2026021122330967700_bib36","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.1111\/j.1462-5822.2010.01505.x","article-title":"Cytosolic phospholipase A2 as a mediator of disease pathogenesis","volume":"12","author":"Linkous","year":"2010","journal-title":"Cell Microbiol"},{"key":"2026021122330967700_bib37","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1016\/j.bbalip.2008.07.007","article-title":"Expression of Ca(2+)-independent and Ca(2+)-dependent phospholipases A(2) and cyclooxygenases in human melanocytes and malignant melanoma cell lines","volume":"1781","author":"Scuderi","year":"2008","journal-title":"Biochim Biophys Acta"},{"key":"2026021122330967700_bib38","doi-asserted-by":"crossref","first-page":"F831","DOI":"10.1152\/ajprenal.00441.2011","article-title":"Human TSC-associated renal angiomyolipoma cells are hypersensitive to ER stress","volume":"303","author":"Siroky","year":"2012","journal-title":"Am J Physiol Renal Physiol"},{"key":"2026021122330967700_bib39","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1084\/jem.20131080","article-title":"Estradiol and mTORC2 cooperate to enhance prostaglandin biosynthesis and tumorigenesis in TSC2-deficient LAM cells","volume":"211","author":"Li","year":"2014","journal-title":"J Exp Med"},{"key":"2026021122330967700_bib40","doi-asserted-by":"crossref","first-page":"e104809","DOI":"10.1371\/journal.pone.0104809","article-title":"Rapamycin-insensitive up-regulation of adipocyte phospholipase A2 in tuberous sclerosis and lymphangioleiomyomatosis","volume":"9","author":"Li","year":"2014","journal-title":"PLoS One"},{"key":"2026021122330967700_bib41","doi-asserted-by":"crossref","first-page":"725","DOI":"10.4161\/auto.5.5.8504","article-title":"Rapamycin inhibits mTORC1, but not completely","volume":"5","author":"Thoreen","year":"2009","journal-title":"Autophagy"},{"key":"2026021122330967700_bib42","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1002\/emmm.201100131","article-title":"Non-canonical functions of the tuberous sclerosis complex-Rheb signalling axis","volume":"3","author":"Neuman","year":"2011","journal-title":"EMBO Mol Med"}],"container-title":["American Journal of Respiratory Cell and Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article-pdf\/53\/1\/33\/66809838\/ajrcmb_53_1_33.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article-pdf\/53\/1\/33\/66809838\/ajrcmb_53_1_33.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T03:34:35Z","timestamp":1770867275000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article\/53\/1\/33\/8467854"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,7,1]]},"references-count":42,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2015,7,1]]},"published-print":{"date-parts":[[2015,7,1]]}},"URL":"https:\/\/doi.org\/10.1165\/rcmb.2014-0379rc","relation":{},"ISSN":["1044-1549","1535-4989"],"issn-type":[{"value":"1044-1549","type":"print"},{"value":"1535-4989","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2015,7]]},"published":{"date-parts":[[2015,7,1]]}}}