Prediction of non-alcoholic fatty-liver disease and liver fat content by serum molecular lipids

Matej Orešič; Tuulia Hyötyläinen; Anna Kotronen; Peddinti Gopalacharyulu; Heli Nygren; Johanna Arola; Sandra Castillo; Ismo Mattila; Antti Hakkarainen; Ronald J.H. Borra; Miikka Juhani Honka; An Verrijken; Sven Francque; Patricia Iozzo; Marja Leivonen; Nabil Jaser; Anne Juuti; Thorkild I.A. Sørensen; Pirjo Nuutila; Luc Van Gaal; Hannele Yki-Järvinen

doi:10.1007/s00125-013-2981-2

Prediction of non-alcoholic fatty-liver disease and liver fat content by serum molecular lipids

Matej Orešič^*
, Tuulia Hyötyläinen
, Anna Kotronen
, Peddinti Gopalacharyulu
, Heli Nygren
, Johanna Arola
, Sandra Castillo
, Ismo Mattila
, Antti Hakkarainen
, Ronald J.H. Borra
, Miikka Juhani Honka
, An Verrijken
, Sven Francque
, Patricia Iozzo
, Marja Leivonen
, Nabil Jaser
, Anne Juuti
, Thorkild I.A. Sørensen
, Pirjo Nuutila
, Luc Van Gaal

Hannele Yki-Järvinen

^*Corresponding author for this work

Research output: Contribution to journal › Article › Scientific › peer-review

148 Citations (Scopus)

Abstract

Aims/hypothesis: We examined whether analysis of lipids by ultra-performance liquid chromatography (UPLC) coupled to MS allows the development of a laboratory test for non-alcoholic fatty-liver disease (NAFLD), and how a lipid-profile biomarker compares with the prediction of NAFLD and liver-fat content based on routinely available clinical and laboratory data. Methods: We analysed the concentrations of molecular lipids by UPLC-MS in blood samples of 679 well-characterised individuals in whom liver-fat content was measured using proton magnetic resonance spectroscopy (¹H-MRS) or liver biopsy. The participants were divided into biomarker-discovery (n = 287) and validation (n = 392) groups to build and validate the diagnostic models, respectively. Results: Individuals with NAFLD had increased triacylglycerols with low carbon number and double-bond content while lysophosphatidylcholines and ether phospholipids were diminished in those with NAFLD. A serum-lipid signature comprising three molecular lipids ('lipid triplet') was developed to estimate the percentage of liver fat. It had a sensitivity of 69.1% and specificity of 73.8% when applied for diagnosis of NAFLD in the validation series. The usefulness of the lipid triplet was demonstrated in a weight-loss intervention study. Conclusions/interpretation: The liver-fat-biomarker signature based on molecular lipids may provide a non-invasive tool to diagnose NAFLD, in addition to highlighting lipid molecular pathways involved in the disease.

Original language	English
Pages (from-to)	2266-2274
Journal	Diabetologia
Volume	56
Issue number	10
DOIs	https://doi.org/10.1007/s00125-013-2981-2
Publication status	Published - 1 Oct 2013
MoE publication type	A1 Journal article-refereed

Funding

Acknowledgements We gratefully acknowledge Mia Urjansson and Katja Sohlo (University of Helsinki, Helsinki, Finland) as well as Anna-Liisa Ruskeepää, Ulla Lahtinen and Tijana Marinković (VTT Technical Research Centre of Finland, Espoo, Finland) for excellent technical assistance, and the volunteers for their help. Funding This study was supported by research grants from the Academy of Finland, the Sigrid Juselius Foundation, the Finnish Diabetes Research Foundation, Emil Aaltonen Foundation, the Finnish Medical Foundation, Novo Nordisk Foundation, and by the Academy of Finland Centre of Excellence in Molecular Systems Immunology and Physiology Research - SyMMyS, 2012–2017, decision number 250114). This work is part of the project ‘Hepatic and adipose tissue and functions in the metabolic syndrome (HEPADIP)’, which is supported by the European Commission as an Integrated Project under the 6th Framework Programme (Contract LSHM-CT-2005-018734). In addition, the research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement number 115372, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007–2013) and EFPIA companies’ in kind contribution.

Keywords

Lipidomics
Mass spectrometry
Non-alcoholic fatty-liver disease

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10.1007/s00125-013-2981-2

Cite this

Orešič, M., Hyötyläinen, T., Kotronen, A., Gopalacharyulu, P., Nygren, H., Arola, J., Castillo, S., Mattila, I., Hakkarainen, A., Borra, R. J. H., Honka, M. J., Verrijken, A., Francque, S., Iozzo, P., Leivonen, M., Jaser, N., Juuti, A., Sørensen, T. I. A., Nuutila, P., ... Yki-Järvinen, H. (2013). Prediction of non-alcoholic fatty-liver disease and liver fat content by serum molecular lipids. Diabetologia, 56(10), 2266-2274. https://doi.org/10.1007/s00125-013-2981-2

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abstract = "Aims/hypothesis: We examined whether analysis of lipids by ultra-performance liquid chromatography (UPLC) coupled to MS allows the development of a laboratory test for non-alcoholic fatty-liver disease (NAFLD), and how a lipid-profile biomarker compares with the prediction of NAFLD and liver-fat content based on routinely available clinical and laboratory data. Methods: We analysed the concentrations of molecular lipids by UPLC-MS in blood samples of 679 well-characterised individuals in whom liver-fat content was measured using proton magnetic resonance spectroscopy (1H-MRS) or liver biopsy. The participants were divided into biomarker-discovery (n = 287) and validation (n = 392) groups to build and validate the diagnostic models, respectively. Results: Individuals with NAFLD had increased triacylglycerols with low carbon number and double-bond content while lysophosphatidylcholines and ether phospholipids were diminished in those with NAFLD. A serum-lipid signature comprising three molecular lipids ('lipid triplet') was developed to estimate the percentage of liver fat. It had a sensitivity of 69.1\% and specificity of 73.8\% when applied for diagnosis of NAFLD in the validation series. The usefulness of the lipid triplet was demonstrated in a weight-loss intervention study. Conclusions/interpretation: The liver-fat-biomarker signature based on molecular lipids may provide a non-invasive tool to diagnose NAFLD, in addition to highlighting lipid molecular pathways involved in the disease.",

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Orešič, M, Hyötyläinen, T, Kotronen, A, Gopalacharyulu, P , Nygren, H, Arola, J, Castillo, S, Mattila, I, Hakkarainen, A, Borra, RJH, Honka, MJ, Verrijken, A, Francque, S, Iozzo, P, Leivonen, M, Jaser, N, Juuti, A, Sørensen, TIA, Nuutila, P, Van Gaal, L & Yki-Järvinen, H 2013, 'Prediction of non-alcoholic fatty-liver disease and liver fat content by serum molecular lipids', Diabetologia, vol. 56, no. 10, pp. 2266-2274. https://doi.org/10.1007/s00125-013-2981-2

TY - JOUR

T1 - Prediction of non-alcoholic fatty-liver disease and liver fat content by serum molecular lipids

AU - Orešič, Matej

AU - Hyötyläinen, Tuulia

AU - Kotronen, Anna

AU - Gopalacharyulu, Peddinti

AU - Nygren, Heli

AU - Arola, Johanna

AU - Castillo, Sandra

AU - Mattila, Ismo

AU - Hakkarainen, Antti

AU - Borra, Ronald J.H.

AU - Honka, Miikka Juhani

AU - Verrijken, An

AU - Francque, Sven

AU - Iozzo, Patricia

AU - Leivonen, Marja

AU - Jaser, Nabil

AU - Juuti, Anne

AU - Sørensen, Thorkild I.A.

AU - Nuutila, Pirjo

AU - Van Gaal, Luc

AU - Yki-Järvinen, Hannele

PY - 2013/10/1

Y1 - 2013/10/1

N2 - Aims/hypothesis: We examined whether analysis of lipids by ultra-performance liquid chromatography (UPLC) coupled to MS allows the development of a laboratory test for non-alcoholic fatty-liver disease (NAFLD), and how a lipid-profile biomarker compares with the prediction of NAFLD and liver-fat content based on routinely available clinical and laboratory data. Methods: We analysed the concentrations of molecular lipids by UPLC-MS in blood samples of 679 well-characterised individuals in whom liver-fat content was measured using proton magnetic resonance spectroscopy (1H-MRS) or liver biopsy. The participants were divided into biomarker-discovery (n = 287) and validation (n = 392) groups to build and validate the diagnostic models, respectively. Results: Individuals with NAFLD had increased triacylglycerols with low carbon number and double-bond content while lysophosphatidylcholines and ether phospholipids were diminished in those with NAFLD. A serum-lipid signature comprising three molecular lipids ('lipid triplet') was developed to estimate the percentage of liver fat. It had a sensitivity of 69.1% and specificity of 73.8% when applied for diagnosis of NAFLD in the validation series. The usefulness of the lipid triplet was demonstrated in a weight-loss intervention study. Conclusions/interpretation: The liver-fat-biomarker signature based on molecular lipids may provide a non-invasive tool to diagnose NAFLD, in addition to highlighting lipid molecular pathways involved in the disease.

AB - Aims/hypothesis: We examined whether analysis of lipids by ultra-performance liquid chromatography (UPLC) coupled to MS allows the development of a laboratory test for non-alcoholic fatty-liver disease (NAFLD), and how a lipid-profile biomarker compares with the prediction of NAFLD and liver-fat content based on routinely available clinical and laboratory data. Methods: We analysed the concentrations of molecular lipids by UPLC-MS in blood samples of 679 well-characterised individuals in whom liver-fat content was measured using proton magnetic resonance spectroscopy (1H-MRS) or liver biopsy. The participants were divided into biomarker-discovery (n = 287) and validation (n = 392) groups to build and validate the diagnostic models, respectively. Results: Individuals with NAFLD had increased triacylglycerols with low carbon number and double-bond content while lysophosphatidylcholines and ether phospholipids were diminished in those with NAFLD. A serum-lipid signature comprising three molecular lipids ('lipid triplet') was developed to estimate the percentage of liver fat. It had a sensitivity of 69.1% and specificity of 73.8% when applied for diagnosis of NAFLD in the validation series. The usefulness of the lipid triplet was demonstrated in a weight-loss intervention study. Conclusions/interpretation: The liver-fat-biomarker signature based on molecular lipids may provide a non-invasive tool to diagnose NAFLD, in addition to highlighting lipid molecular pathways involved in the disease.

KW - Lipidomics

KW - Mass spectrometry

KW - Non-alcoholic fatty-liver disease

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SN - 0012-186X

VL - 56

SP - 2266

EP - 2274

JO - Diabetologia

JF - Diabetologia

IS - 10

ER -

Prediction of non-alcoholic fatty-liver disease and liver fat content by serum molecular lipids

Abstract

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Keywords

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