Lipidomic Approaches to Study HDL Metabolism in Patients with Central Obesity Diagnosed with Metabolic Syndrome

Gabriele Mocciaro, Simona D’amore, Benjamin Jenkins, Richard Kay, Antonio Murgia, Luis Vicente Herrera‐marcos, Stefanie Neun, Alice P. Sowton, Zoe Hall, Susana Alejandra Palma‐duran, Giuseppe Palasciano, Frank Reimann, Andrew Murray, Patrizia Suppressa, Carlo Sabbà, Antonio Moschetta, Albert Koulman, Julian L. Griffin*, Michele Vacca

*Corresponding author for this work

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Abstract

The metabolic syndrome (MetS) is a cluster of cardiovascular risk factors characterised by central obesity, atherogenic dyslipidaemia, and changes in the circulating lipidome; the underlying mechanisms that lead to this lipid remodelling have only been partially elucidated. This study used an integrated “omics” approach (untargeted whole serum lipidomics, targeted proteomics, and lipoprotein lipidomics) to study lipoprotein remodelling and HDL composition in subjects with central obesity diagnosed with MetS (vs. controls). Compared with healthy subjects, MetS patients showed higher free fatty acids, diglycerides, phosphatidylcholines, and triglycerides, particularly those enriched in products of de novo lipogenesis. On the other hand, the “lysophosphatidylcholines to phosphatidylcholines” and “cholesteryl ester to free cholesterol” ratios were reduced, pointing to a lower activity of lecithin cholesterol acyltransferase (LCAT) in MetS; LCAT activity (directly measured and predicted by lipidomic ratios) was positively correlated with high‐density lipoprotein cholesterol (HDL‐C) and negatively correlated with body mass index (BMI) and insulin resistance. Moreover, many phosphatidylcholines and sphingomyelins were significantly lower in the HDL of MetS patients and strongly correlated with BMI and clinical metabolic parameters. These results suggest that MetS is associated with an impairment of phospholipid metabolism in HDL, partially led by LCAT, and associated with obesity and underlying insulin resistance. This study proposes a candidate strategy to use integrated “omics” approaches to gain mechanistic insights into lipoprotein remodelling, thus deepening the knowledge regarding the molecular basis of the association between MetS and atherosclerosis.

Original languageEnglish
Article number6786
JournalInternational Journal of Molecular Sciences
Volume23
Issue number12
DOIs
Publication statusPublished - 17 Jun 2022

Bibliographical note

Funding Information:
G.M.: M.V., and J.L.G. were funded by the Medical Research Council (MRC) (Lipid Profiling and Signalling, MC UP A90 1006 & Lipid Dynamics and Regulation, MC PC 13030). M.V. is supported by the University of Bari (Horizon Europe Seed cod. id. S06‐miRNASH) and by the Foundation for Liver Research. G.M. was also partly funded by NIHR Cambridge Biomedical Research Centre (Gastroenterology Theme). A.K. and B.J. are supported by the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (IS‐BRC‐1215‐20014). S.N. received a studentship from AstraZeneca. R.K. and F.R. contributions were supported by Wellcome Trust (WT220271), the BRC and the MRC (MRC_MC_UU_12012/3 and MR/M009041/1). Z.H. is supported by the Royal Society and a CAMS‐UK fellowship. A.P.S is supported by the BHF grant FS/17/61/33473.

Funding Information:
Funding: G.M.: M.V., and J.L.G. were funded by the Medical Research Council (MRC) (Lipid Pro‐ filing and Signalling, MC UP A90 1006 & Lipid Dynamics and Regulation, MC PC 13030). M.V. is supported by the University of Bari (Horizon Europe Seed cod. id. S06‐miRNASH) and by the Foun‐ dation for Liver Research. G.M. was also partly funded by NIHR Cambridge Biomedical Research Centre (Gastroenterology Theme). A.K. and B.J. are supported by the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (IS‐BRC‐1215‐20014). S.N. received a stu‐ dentship from AstraZeneca. R.K. and F.R. contributions were supported by Wellcome Trust (WT220271), the BRC and the MRC (MRC_MC_UU_12012/3 and MR/M009041/1). Z.H. is supported by the Royal Society and a CAMS‐UK fellowship. A.P.S is supported by the BHF grant FS/17/61/33473.

Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

  • LC‐MS
  • lecithin cholesterol acyltransferase (LCAT)
  • lipidomics
  • lipoprotein metabolism
  • obesity

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