PMID- 32467337 OWN - NLM STAT- MEDLINE DCOM- 20200820 LR - 20211204 IS - 1468-3296 (Electronic) IS - 0040-6376 (Linking) VI - 75 IP - 8 DP - 2020 Aug TI - Sphingolipid, fatty acid and phospholipid metabolites are associated with disease severity and mTOR inhibition in lymphangioleiomyomatosis. PG - 679-688 LID - 10.1136/thoraxjnl-2019-214241 [doi] AB - BACKGROUND: Lymphangioleiomyomatosis (LAM) is a rare multisystem disease almost exclusively affecting women which causes loss of lung function, lymphatic abnormalities and angiomyolipomas. LAM occurs sporadically and in people with tuberous sclerosis complex (TSC). Loss of TSC gene function leads to dysregulated mechanistic target of rapamycin (mTOR) signalling. As mTOR is a regulator of lipid and nucleotide synthesis, we hypothesised that the serum metabolome would be altered in LAM and related to disease severity and activity. METHODS: Ultrahigh performance liquid chromatography-tandem mass spectroscopy was used to examine the serum metabolome of 79 closely phenotyped women with LAM, including 29 receiving treatment with an mTOR inhibitor and 43 healthy control women. RESULTS: Sphingolipid, fatty acid and phospholipid metabolites were associated with FEV(1) in women with LAM (eg, behenoyl sphingomyelin adjusted (adj.) p=8.10 x 10(-3)). Those with higher disease-burden scores had abnormalities in fatty acid, phospholipid and lysolipids. Rate of loss of FEV(1) was associated with differences in acyl-carnitine, acyl-glycines, acyl-glutamine, fatty acids, endocanbinoids and sphingolipids (eg, myristoleoylcarnitine adj. p=0.07). In TSC-LAM, rapamycin affected modules of interrelated metabolites which comprised linoleic acid, the tricarboxylic acid cycle, aminoacyl-tRNA biosynthesis, cysteine, methionine, arginine and proline metabolism. Metabolomic pathway analysis within modules reiterated the importance of glycerophospholipid metabolites (adj. p=0.047). CONCLUSIONS: Women with LAM have altered lipid metabolism. The associations between these metabolites, multiple markers of disease activity and their potential biological roles in cell survival and signalling, suggest that lipid species may be both disease-relevant biomarkers and potential therapeutic targets for LAM. CI - (c) Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ. FAU - Bottolo, Leonardo AU - Bottolo L AD - Department of Medical Genetics, University of Cambridge, Cambridge, UK. AD - The Alan Turing Institute, London, UK. AD - MRC Biostatistics Unit, Cambridge, UK. FAU - Miller, Suzanne AU - Miller S AD - Division of Respiratory Medicine, NIHR Biomedical Research Centre, Biodiscovery Institute and Nottingham Molecular Pathology Node, University of Nottingham, Nottingham, UK. FAU - Johnson, Simon R AU - Johnson SR AUID- ORCID: 0000-0002-9837-2763 AD - Division of Respiratory Medicine, NIHR Biomedical Research Centre, Biodiscovery Institute and Nottingham Molecular Pathology Node, University of Nottingham, Nottingham, UK simon.johnson@nottingham.ac.uk. AD - National Centre for Lymphangioleiomyomatosis, Nottingham University Hospitals NHS Trust, Nottingham, UK. LA - eng GR - MR/T002042/1/MRC_/Medical Research Council/United Kingdom PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200528 PL - England TA - Thorax JT - Thorax JID - 0417353 RN - 0 (Fatty Acids) RN - 0 (Immunosuppressive Agents) RN - 0 (Phospholipids) RN - 0 (Sphingolipids) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Adult MH - Case-Control Studies MH - Fatty Acids/*blood MH - Female MH - Humans MH - Immunosuppressive Agents/therapeutic use MH - Lymphangioleiomyomatosis/*blood/*drug therapy MH - Phospholipids/*blood MH - Sirolimus/therapeutic use MH - Sphingolipids/*blood MH - TOR Serine-Threonine Kinases/*antagonists & inhibitors OTO - NOTNLM OT - rare lung diseases COIS- Competing interests: SRJ reports grants from the National Institute for Health Research, The LAM Foundation, LAM Action during the conduct of the study and personal fees from Pfizer, outside the submitted work. EDAT- 2020/05/30 06:00 MHDA- 2020/08/21 06:00 CRDT- 2020/05/30 06:00 PHST- 2019/10/23 00:00 [received] PHST- 2020/03/26 00:00 [revised] PHST- 2020/04/16 00:00 [accepted] PHST- 2020/05/30 06:00 [pubmed] PHST- 2020/08/21 06:00 [medline] PHST- 2020/05/30 06:00 [entrez] AID - thoraxjnl-2019-214241 [pii] AID - 10.1136/thoraxjnl-2019-214241 [doi] PST - ppublish SO - Thorax. 2020 Aug;75(8):679-688. doi: 10.1136/thoraxjnl-2019-214241. Epub 2020 May 28.