Plasma Metabolomic and Lipidomic Profiling of Metabolic Dysfunction-Associated Fatty Liver Disease in Humans Using an Untargeted Multiplatform Approach

Xiangping Lin; Xinyu Liu; Mohamed N Triba; Nadia Bouchemal; Zhicheng Liu; Douglas I Walker; Tony Palama; Laurence Le Moyec; Marianne Ziol; Nada Helmy; Corinne Vons; Guowang Xu; Carina Prip-Buus; Philippe Savarin

doi:10.3390/metabo12111081

Plasma Metabolomic and Lipidomic Profiling of Metabolic Dysfunction-Associated Fatty Liver Disease in Humans Using an Untargeted Multiplatform Approach

Metabolites. 2022 Nov 8;12(11):1081. doi: 10.3390/metabo12111081.

Authors

Xiangping Lin^{1

2}, Xinyu Liu², Mohamed N Triba¹, Nadia Bouchemal¹, Zhicheng Liu³, Douglas I Walker⁴, Tony Palama¹, Laurence Le Moyec^{5

6}, Marianne Ziol⁷, Nada Helmy⁸, Corinne Vons⁸, Guowang Xu², Carina Prip-Buus⁹, Philippe Savarin¹

Affiliations

¹ Sorbonne Paris Nord University, Chemistry Structures Properties of Biomaterials and Therapeutic Agents Laboratory (CSPBAT), Nanomédecine Biomarqueurs Détection Team (NBD), The National Center for Scientific Research (CNRS), UMR 7244, 74 Rue Marcel Cachin, CEDEX, 93017 Bobigny, France.
² CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.
³ School of Pharmacy, Anhui Medical University, Hefei 230032, China.
⁴ Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁵ Unité de Biologie Intégrative des Adaptations à l'Exercice (UBIAE), Université d'Evry Val d'Essonne-Université Paris-Saclay, 91000 Evry, France.
⁶ Muséum National d'Histoire Naturelle, Unité MCAM, UMR 7245, CNRS, 75005 Paris, France.
⁷ Department of Pathology, University Hospital Jean Verdier, Assistance Publique-Hôpitaux de Paris, 93140 Paris, France.
⁸ Department of Digestive and Metabolic Surgery, Jean Verdier Hospital, Paris XIII University-University Hospitals of Paris Seine Saint-Denis, 93140 Paris, France.
⁹ Université Paris Cité, CNRS, INSERM, Institut Cochin, 75014 Paris, France.

Abstract

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a complex disorder that is implicated in dysregulations in multiple biological pathways, orchestrated by interactions between genetic predisposition, metabolic syndromes and environmental factors. The limited knowledge of its pathogenesis is one of the bottlenecks in the development of prognostic and therapeutic options for MAFLD. Moreover, the extent to which metabolic pathways are altered due to ongoing hepatic steatosis, inflammation and fibrosis and subsequent liver damage remains unclear. To uncover potential MAFLD pathogenesis in humans, we employed an untargeted nuclear magnetic resonance (NMR) spectroscopy- and high-resolution mass spectrometry (HRMS)-based multiplatform approach combined with a computational multiblock omics framework to characterize the plasma metabolomes and lipidomes of obese patients without (n = 19) or with liver biopsy confirmed MAFLD (n = 63). Metabolite features associated with MAFLD were identified using a metabolome-wide association study pipeline that tested for the relationships between feature responses and MAFLD. A metabolic pathway enrichment analysis revealed 16 pathways associated with MAFLD and highlighted pathway changes, including amino acid metabolism, bile acid metabolism, carnitine shuttle, fatty acid metabolism, glycerophospholipid metabolism, arachidonic acid metabolism and steroid metabolism. These results suggested that there were alterations in energy metabolism, specifically amino acid and lipid metabolism, and pointed to the pathways being implicated in alerted liver function, mitochondrial dysfunctions and immune system disorders, which have previously been linked to MAFLD in human and animal studies. Together, this study revealed specific metabolic alterations associated with MAFLD and supported the idea that MAFLD is fundamentally a metabolism-related disorder, thereby providing new perspectives for diagnostic and therapeutic strategies.

Keywords: NMR; lipidomics; mass spectrometry; metabolic dysfunction-associated fatty liver disease; metabolomics; multiblock analysis.

Grants and funding

This study was supported by the French Ministry of Higher Education, Research and Innovation (PhD grant for P.S.), grants from the Association Française pour l’Etude du Foie (AFEF-Gilead Sciences 2012), from the Ligue National Contre le Cancer and the Université Sorbonne Paris Cité (IDEX-2015 OBELIX) and the National Natural Science Foundation of China (21934006 and 21876169 for G.X.). We acknowledge the NMR-PF facility (Sorbonne Paris Nord University, Villetaneuse, France) and the IFRB for their support of the project. N.H. was supported by a fellowship from the Société Francophone du Diabète (SFD 2014). The funders had no role in the design, analysis or writing of this article.