Non-alcoholic fatty liver disease is characterised by a reduced polyunsaturated fatty acid transport via free fatty acids and high-density lipoproteins (HDL)

Gabriele Mocciaro, Michael Allison, Benjamin Jenkins, Vian Azzu, Isabel Huang-Doran, Luis Vicente Herrera-Marcos, Zoe Hall, Antonio Murgia, Davies Susan, Mattia Frontini, Antonio Vidal-Puig, Albert Koulman*, Julian L. Griffin*, Michele Vacca*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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Abstract

Background and objectives: Non-alcoholic fatty liver disease (NAFLD) develops due to impaired hepatic lipid fluxes and is a risk factor for chronic liver disease and atherosclerosis. Lipidomic studies consistently reported characteristic hepatic/VLDL “lipid signatures” in NAFLD; whole plasma traits are more debated. Surprisingly, the HDL lipid composition by mass spectrometry has not been characterised across the NAFLD spectrum, despite HDL being a possible source of hepatic lipids delivered from peripheral tissues alongside free fatty acids (FFA). This study characterises the HDL lipidomic signature in NAFLD, and its correlation with metabolic and liver disease markers. Methods: We used liquid chromatography-mass spectrometry to determine the whole serum and HDL lipidomic profile in 89 biopsy-proven NAFLD patients and 20 sex and age-matched controls. Results: In the whole serum of NAFLD versus controls, we report a depletion in polyunsaturated (PUFA) phospholipids (PL) and FFA; with PUFA PL being also lower in HDL, and negatively correlated with BMI, insulin resistance, triglycerides, and hepatocyte ballooning. In the HDL of the NAFLD group we also describe higher saturated ceramides, which positively correlate with insulin resistance and transaminases. Conclusion: NAFLD features lower serum lipid species containing polyunsaturated fatty acids; the most affected lipid fractions are FFA and (HDL) phospholipids; our data suggest a possible defect in the transfer of PUFA from peripheral tissues to the liver in NAFLD. Mechanistic studies are required to explore the biological implications of our findings addressing if HDL composition can influence liver metabolism and damage, thus contributing to NAFLD pathophysiology.

Original languageEnglish
Article number101728
JournalMolecular Metabolism
Volume73
Early online date2 May 2023
DOIs
Publication statusPublished - Jul 2023

Bibliographical note

Funding Information: The cohort was initially generated with the support of the Evelyn Trust (to M.A.). G.M., Z.H., 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 to J.L.G.; MR/W019132/1 to Z.H.) . MV is supported by the University of Bari (Horizon Europe Seed cod. id. S06-miRNASH) , the Foundation for Liver Research (Intramural Funding) , Associazione Italiana Ricerca sul Cancro ( IG2022 Grant n. 27521 ) and Ministry of University and Research on Next Generation EU Funds ( Cod PE00000003 , CUP: H93C22000630001 , DD MUR 1550 , Title: “ON Foods - Research and innovation network on food and nutrition Sustainability, Safety and Security – Working ON Foods” ; Cod: CN00000041 , CUP: H93C22000430007 , Title PNRR “National Center for Gene Therapy and Drugs based on RNA Technology”, M4C2-Investimento 1.4 ; Code: CN00000013 , CUP: H93C22000450007 , Title PNRR: “National Centre for HPC, Big Data and Quantum Computing” ). G.M. was also partly funded by NIHR Cambridge Biomedical Research Centre and the Foundation for Liver Research . A.K. and B.J. are supported by the National Institute for Health Research Cambridge Biomedical Research Centre (IS-BRC-1215-20014). M.F. is funded by the British Heart Foundation (FS/18/53/33863) and is supported by the National Institute for Health and Care Research Exeter Biomedical Research Centre . The views expressed are those of the author(s) and not necessarily those of the funders (e.g. NIHR or the Department of Health and Social Care). V.A. was funded by the University of Cambridge , the Mason Medical Research Trust , the Academy of Medical Sciences and the NIHR Cambridge Biomedical Research Centre.

Publisher Copyright: © 2023

Data Availability Statement

Data will be made available on request.

Keywords

  • LC-MS
  • Lipidomics
  • Lipoprotein metabolism
  • Non-alcoholic fatty liver disease (NAFLD)
  • Obesity

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