title: Tuberous sclerosis complex 2 loss increases lysophosphatidylcholine synthesis in lymphangioleiomyomatosis.
abstract: 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-based 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.
authors.affiliation: 1 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Carmen
authors.initials: C
authors.lastname: Priolo
authors.affiliation: 2 Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, Massachusetts; and.
authors.forename: Stéphane J H
authors.initials: SJ
authors.lastname: Ricoult
authors.affiliation: 1 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Damir
authors.initials: D
authors.lastname: Khabibullin
authors.affiliation: 1 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Harilaos
authors.initials: H
authors.lastname: Filippakis
authors.affiliation: 1 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Jane
authors.initials: J
authors.lastname: Yu
authors.affiliation: 2 Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, Massachusetts; and.
authors.forename: Brendan D
authors.initials: BD
authors.lastname: Manning
authors.affiliation: 3 Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Clary
authors.initials: C
authors.lastname: Clish
authors.affiliation: 1 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Elizabeth P
authors.initials: EP
authors.lastname: Henske
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D050356:Lipid Metabolism; D018192:Lymphangioleiomyomatosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008244:Lysophosphatidylcholines / Q000096:biosynthesis* / Q000235:genetics; D013058:Mass Spectrometry; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D009287:Naphthyridines / Q000494:pharmacology; D054467:Phospholipases A2 / Q000235:genetics / Q000378:metabolism; D051381:Rats; D020123:Sirolimus / Q000494:pharmacology; D051779:Sterol Regulatory Element Binding Proteins / Q000235:genetics / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000172:deficiency*
chemical_list: C553294:1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo(h)(1,6)naphthyridin-2(1H)-one; D000903:Antibiotics, Antineoplastic; D008244:Lysophosphatidylcholines; D046912:Multiprotein Complexes; D009287:Naphthyridines; D051779:Sterol Regulatory Element Binding Proteins; C000624653:TSC2 protein, human; C000624654:Tsc2 protein, mouse; C000624655:Tsc2 protein, rat; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D054467:Phospholipases A2; D020123:Sirolimus
keywords: lipidomics; mTORC1; mass spectrometry; phospholipase