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Sphingolipid, fatty acid and phospholipid metabolites are associated with disease severity and mTOR inhibition in lymphangioleiomyomatosis
  1. Leonardo Bottolo1,2,3,
  2. Suzanne Miller4,
  3. Simon R Johnson4,5
  1. 1 Department of Medical Genetics, University of Cambridge, Cambridge, UK
  2. 2 The Alan Turing Institute, London, UK
  3. 3 MRC Biostatistics Unit, Cambridge, UK
  4. 4 Division of Respiratory Medicine, NIHR Biomedical Research Centre, Biodiscovery Institute and Nottingham Molecular Pathology Node, University of Nottingham, Nottingham, UK
  5. 5 National Centre for Lymphangioleiomyomatosis, Nottingham University Hospitals NHS Trust, Nottingham, UK
  1. Correspondence to Professor Simon R Johnson, Division of Respiratory Medicine, NIHR Biomedical Research Centre and Nottingham Molecular Pathology Node, University of Nottingham, Nottingham NG7 2UH, UK; simon.johnson{at}


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 FEV1 in women with LAM (eg, behenoyl sphingomyelin adjusted (adj.) p=8.10 × 10-3). Those with higher disease-burden scores had abnormalities in fatty acid, phospholipid and lysolipids. Rate of loss of FEV1 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.

  • rare lung diseases

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  • Contributors LB performed the data analysis, produced the figures and co-wrote the paper. SM processed the samples and coordinated the clinical data. SRJ conceived the study, saw the patients co-wrote the paper and acts as guarantor for the study.

  • Funding Alan Turing Institute under the Engineering and Physical Sciences Research Council(EP/N510129/1 to L.B.). NIHR RD-TRC and MRC/EPSRC Nottingham Molecular Pathology Node(MR/N005953/1)

  • 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.

  • Patient consent for publication Obtained

  • Ethics approval The study was approved by the East Midlands Research Ethics Committee (13/EM/0264). The use of control samples was approved by Nottingham University Ethics Committee (approval BT A27 08 2009).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.

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