1. The Altered Serum Lipidome and its Diagnostic Potential for Non-Alcoholic Fatty Liver (NAFL)-Associated Hepatocellular Carcinoma
- Author
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Malte P. Suppli, Cristina Alonso, Bruno Sangro, Ekaterina Zhuravleva, Rocio I.R. Macias, Filip K. Knop, Emma Eizaguirre, Manuel Romero-Gómez, Jesus M. Banales, Alvaro Santos-Laso, Raul Jimenez-Agüero, Jesper B. Andersen, Marco Arrese Jimenez, Monika Lewinska, Stine Karlsen Oversoe, Flair José Carrilho, Gerda Elisabeth Villadsen, María Jesús Pareja, Claudia Pms de Oliveira, Thomas Decaens, Enara Arretxe, European Commission, Novo Nordisk Foundation, Danish Cancer Society Research Center, Danish Medical Research Council, Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (España), Ikerbasque Basque Foundation for Science, Fundación Vasca de Innovación e Investigación Sanitarias, Eusko Jaurlaritza, RIS3 Euskadi, Fundación Científica Asociación Española Contra el Cáncer, Fondo Nacional de Desarrollo Científico y Tecnológico (Chile), and Comisión Nacional de Investigación Científica y Tecnológica (Chile)
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PC, phosphatidylcholines ,Medicine (General) ,History ,Polymers and Plastics ,Disease ,Gastroenterology ,NAE, N-acyl ethanolamines ,LPC, lysophosphatidylcholines ,0302 clinical medicine ,SM, sphingomyelins ,OB-NAFLD, morbidly obese bariatric surgery NAFLD ,HCC ,050207 economics ,chemistry.chemical_classification ,0303 health sciences ,AFP, alpha-fetoprotein ,CMH, monohexylceramides ,Liver Neoplasms/blood ,Liver Neoplasms ,food and beverages ,General Medicine ,Lipidome ,TG, triglycerides ,Prognosis ,Lipids ,PE, phosphatidylethanolamines ,3. Good health ,Medicine ,030211 gastroenterology & hepatology ,BCAAs, branch-chain amino acids ,Lipidomics/methods ,medicine.medical_specialty ,Carcinoma, Hepatocellular ,AC, acylcarnitines ,digestive system ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,R5-920 ,NAFLD ,0502 economics and business ,NAFL, non-alcoholic fatty liver ,Humans ,Business and International Management ,PI, phosphatidylinositols ,S1P, sphingosine-1-phosphate ,Fatty acid ,nutritional and metabolic diseases ,medicine.disease ,LPE, lysophosphatidylethanolamines ,Carcinoma, Hepatocellular/blood ,digestive system diseases ,chemistry ,Non-alcoholic Fatty Liver Disease/blood ,Case-Control Studies ,Etiology ,Gene Expression Profiling/methods ,Metabolic syndrome ,MUFA, monounsaturated fatty acids ,Biomarkers ,BMI, body mass index ,LPI, lysophosphatidylinositols ,Industrial and Manufacturing Engineering ,Workflow ,ArAA, aromatic amino acids ,AA, amino acids ,Non-alcoholic Fatty Liver Disease ,biomarker discovery ,NAS, non-alcoholic steatohepatitis ,AV-HCC, alcohol- and viral-associated HCC ,oxFA, oxidized fatty acids ,PUFA, polyunsaturated fatty acids ,050208 finance ,05 social sciences ,Fatty liver ,Institutional review board ,metabolomics ,DEM, differentially expressed metabolites ,BA, bile acids ,Hepatocellular carcinoma ,CTRL, control ,Alpha-fetoprotein ,Viral hepatitis ,DG, diglycerides ,Polyunsaturated fatty acid ,Research Paper ,NAFLD, non-alcoholic fatty liver disease ,ChoE, cholesteryl esters ,Internal medicine ,Lipidomics ,medicine ,Cer, ceramides ,030304 developmental biology ,Lipids/blood ,business.industry ,Gene Expression Profiling ,Reproducibility of Results ,Cancer ,ROC Curve ,SFA, saturated fatty acids ,lipidomics ,business - Abstract
[Background] Non-alcoholic fatty liver disease (NAFLD) is affecting more people globally. Indeed, NAFLD is a spectrum of metabolic dysfunctions that can progress to hepatocellular carcinoma (NAFLD-HCC). This development can occur in a non-cirrhotic liver and thus, often lack clinical surveillance. The aim of this study was to develop non-invasive surveillance method for NAFLD-HCC., [Methods] Using comprehensive ultra-high-performance liquid chromatography mass-spectrometry, we investigated 1,295 metabolites in serum from 249 patients. Area under the receiver operating characteristic curve was calculated for all detected metabolites and used to establish their diagnostic potential. Logistic regression analysis was used to establish the diagnostic score., [Findings] We show that NAFLD-HCC is characterised by a complete rearrangement of the serum lipidome, which distinguishes NAFLD-HCC from non-cancerous individuals and other HCC patients. We used machine learning to build a diagnostic model for NAFLD-HCC. We quantified predictive metabolites and developed the NAFLD-HCC Diagnostic Score (NHDS), presenting superior diagnostic potential compared to alpha-fetoprotein (AFP). Patients’ metabolic landscapes show a progressive depletion in unsaturated fatty acids and acylcarnitines during transformation. Upregulation of fatty acid transporters in NAFLD-HCC tumours contribute to fatty acid depletion in the serum., [Interpretation] NAFLD-HCC patients can be efficiently distinguished by serum metabolic alterations from the healthy population and from HCC patients related to other aetiologies (alcohol and viral hepatitis). Our model can be used for non-invasive surveillance of individuals with metabolic syndrome(s), allowing for early detection of NAFLD-HCC. Therefore, serum metabolomics may provide valuable insight to monitor patients at risk, including morbidly obese, diabetics, and NAFLD patients., We thank all funding sources: The laboratory of JBA is supported by the Novo Nordisk Foundation (14040, 0058419), Danish Cancer Society (R98-A6446, R167-A10784, R278-A16638), and the Danish Medical Research Council (4183-00118A, 1030-00070B). Data used for validation in this study provided by JMB was funded by the Spanish Ministry of Economy and Competitiveness and ’Instituto de Salud Carlos III’ grants (PI18/01075, Miguel Servet Programme CON14/00129 and CPII19/00008) co-financed by ’Fondo Europeo de Desarrollo Regional’ (FEDER); CIBERehd, Spain; IKERBASQUE, Basque foundation for Science, Spain; BIOEF (Basque Foundation for Innovation and Health Research: EiTB Maratoia BIO15/CA/016/BD); Department of Health of the Basque Country (2017111010), Euskadi RIS3 (2019222054, 2020333010); Department of Industry of the Basque Country (Elkartek: KK-2020/00008), AECC Scientific Foundation and European Commission Horizon 2020 program (ESCALON project no.: 825510). Similarly, MAJ was funded by grants from the Fondo Nacional De Ciencia y Tecnología de Chile (FONDECYT #1191145 to M.A.) and the Comisión Nacional de Investigación, Ciencia y Tecnología (CONICYT, AFB170005, CARE Chile UC).
- Published
- 2021
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