Hepatic triglyceride content is intricately associated with numerous metabolites and biochemical pathways
Liver International, vol. 43, pp. 1458–1472
Abstract
BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) is characterized by the pathological accumulation of triglycerides in hepatocytes and is associated with insulin resistance, atherogenic dyslipidaemia and cardiometabolic diseases. Thus far, the extent of metabolic dysregulation associated with hepatic triglyceride accumulation has not been fully addressed. In this study, we aimed to identify metabolites associated with hepatic triglyceride content (HTGC) and map these associations using network analysis. METHODS: To gain insight in the spectrum of metabolites associated with hepatic triglyceride accumulation, we performed a comprehensive plasma metabolomics screening of 1363 metabolites in apparently healthy middle aged (age 45-65) individuals (N = 496) in whom HTGC was measured by proton magnetic resonance spectroscopy. An atlas of metabolite-HTGC associations, based on univariate results, was created using correlation-based Gaussian graphical model (GGM) and genome scale metabolic model network analyses. Pathways associated with the clinical prognosis marker fibrosis 4 (FIB-4) index were tested using a closed global test. RESULTS: ), including 106 endogenous, 1 xenobiotic and 11 partially characterized/uncharacterized metabolites. These associations were mapped to several biological pathways including branched amino acids (BCAA), diglycerols, sphingomyelin, glucosyl-ceramide and lactosyl-ceramide. We also identified a novel possible HTGC-related pathway connecting glutamate, metabolonic lactone sulphate and X-15245 using the GGM network. These pathways were confirmed to be associated with the FIB-4 index as well. The full interactive metabolite-HTGC atlas is provided online: https://tofaquih.github.io/AtlasLiver/. CONCLUSIONS: The combined network and pathway analyses indicated extensive associations between BCAA and the lipids pathways with HTGC and the FIB-4 index. Moreover, we report a novel pathway glutamate-metabolonic lactone sulphate-X-15245 with a potential strong association with HTGC. These findings can aid elucidating HTGC metabolomic profiles and provide insight into novel drug targets for fibrosis-related outcomes.
Authors 14
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Tariq O. Faquih Aachen Department of Clinical Epidemiology Leiden University Medical Center Leiden The Netherlands Department of Clinical Epidemiology
Leiden University Medical Center
Affiliation as printed
Department of Clinical Epidemiology Leiden University Medical Center Leiden the Netherlands
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands
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Jan Bert van Klinken Aachen Department of Human Genetics Leiden University Medical Center Leiden The Netherlands Department of Human Genetics
Leiden University Medical Center · Amsterdam University Medical Centers · Amsterdam Gastroenterology Endocrinology Metabolism · University of Amsterdam
Affiliation as printed
Department of Human Genetics Leiden University Medical Center Leiden the Netherlands
Department of Pediatrics, Amsterdam UMC University of Amsterdam Amsterdam the Netherlands
Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC University of Amsterdam Amsterdam the Netherlands
Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
Department of Pediatrics, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
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Ruifang Li‐Gao Aachen Department of Clinical Epidemiology Leiden University Medical Center Leiden The Netherlands Department of Clinical Epidemiology
Leiden University Medical Center · Metabolon (United States)
Affiliation as printed
Department of Clinical Epidemiology Leiden University Medical Center Leiden the Netherlands
Metabolon, Inc. Morrisville North Carolina USA
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands
Metabolon, Inc., Morrisville, North Carolina, USA
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Raymond Noordam Aachen Department of Internal Medicine Section of Gerontology and Geriatrics Leiden University Medical Center Leiden The Netherlands Section of Gerontology and Geriatrics
Leiden University Medical Center
Affiliation as printed
Department of Internal Medicine, Section of Gerontology and Geriatrics Leiden University Medical Center Leiden the Netherlands
Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands
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Diana van Heemst Aachen Department of Internal Medicine Section of Gerontology and Geriatrics Leiden University Medical Center Leiden The Netherlands Section of Gerontology and Geriatrics
Leiden University Medical Center
Affiliation as printed
Department of Internal Medicine, Section of Gerontology and Geriatrics Leiden University Medical Center Leiden the Netherlands
Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands
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Sebastiaan C. Boone Aachen Department of Clinical Epidemiology Leiden University Medical Center Leiden The Netherlands Department of Clinical Epidemiology
Leiden University Medical Center
Affiliation as printed
Department of Clinical Epidemiology Leiden University Medical Center Leiden the Netherlands
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands
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Affiliation as printed
Metabolon, Inc. Morrisville North Carolina USA
Metabolon, Inc., Morrisville, North Carolina, USA
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Affiliation as printed
Metabolon, Inc. Morrisville North Carolina USA
Metabolon, Inc., Morrisville, North Carolina, USA
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Hildo J. Lamb Aachen Department of Radiology Leiden University Medical Center Leiden The Netherlands Department of Radiology, Leiden University Medical Center
Leiden University Medical Center
Affiliation as printed
Department of Radiology Leiden University Medical Center Leiden the Netherlands
Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands
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Renée de Mutsert Aachen Department of Clinical Epidemiology Leiden University Medical Center Leiden The Netherlands Department of Clinical Epidemiology
Leiden University Medical Center
Affiliation as printed
Department of Clinical Epidemiology Leiden University Medical Center Leiden the Netherlands
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands
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Frits Richard Rosendaal Aachen Department of Clinical Epidemiology Leiden University Medical Center Leiden The Netherlands Department of Clinical Epidemiology
Leiden University Medical Center
Affiliation as printed
Department of Clinical Epidemiology Leiden University Medical Center Leiden the Netherlands
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands
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Astrid van Hylckama Vlieg Aachen Department of Clinical Epidemiology Leiden University Medical Center Leiden The Netherlands Department of Clinical Epidemiology
Leiden University Medical Center
Affiliation as printed
Department of Clinical Epidemiology Leiden University Medical Center Leiden the Netherlands
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands
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Ko Willems van Dijk Aachen Department of Human Genetics Leiden University Medical Center Leiden The Netherlands Department of Internal Medicine Division of Endocrinology Leiden University Medical Center Leiden The Netherlands Department of Human Genetics Division of Endocrinology, Leiden University Medical Center Einthoven Laboratory for Experimental Vascular Medicine
Leiden University Medical Center
Affiliation as printed
Department of Human Genetics Leiden University Medical Center Leiden the Netherlands
Department of Internal Medicine, Division of Endocrinology Leiden University Medical Center Leiden the Netherlands
Einthoven Laboratory for Experimental Vascular Medicine Leiden University Medical Center Leiden the Netherlands
Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
Department of Internal Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, the Netherlands
Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands
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Dennis O. Mook‐Kanamori corresponding Aachen Department of Clinical Epidemiology Leiden University Medical Center Leiden The Netherlands Department of Public Health and Primary Care Leiden University Medical Center Leiden the Netherlands Department of Clinical Epidemiology Department of Public Health and Primary Care
Leiden University Medical Center
Affiliation as printed
Department of Clinical Epidemiology Leiden University Medical Center Leiden the Netherlands
Department of Public Health and Primary Care Leiden University Medical Center Leiden the Netherlands
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands
Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, the Netherlands
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