Noemí Cabré1,2, Fedra Luciano-Mateo1,2, Gerard Baiges-Gayà1,2, Salvador Fernández-Arroyo1,2, Elisabet Rodríguez-Tomàs1,2, Anna Hernández-Aguilera1,2, Marta París3, Fàtima Sabench3, Daniel Del Castillo3, José López-Miranda4, Javier A Menéndez5,6, Jordi Camps1,2, Jorge Joven1,2,7. 1. Department of Medicine and Surgery, Universitat Rovira i Virgili, Reus, Spain. 2. Unitat de Recerca Biomèdica (URB-CRB), Hospital Universitari de Sant Joan, Institut d'Investigacio Sanitaria Pere Virgili, Universitat Rovira i Virgili, Reus, Spain. 3. Department of Surgery, Hospital Universitari de Sant Joan, Institut d'Investigació Sanitaria Pere Virgili, Universitat Rovira i Virgili, Reus, Spain. 4. CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Cordoba, Spain. 5. Program Against Cancer Therapeutic Resistance (ProCURE), Metabolism and Cancer Group, Catalan Institute of Oncology, Girona, Spain. 6. Girona Biomedical Research Institute (IDIBGI), Girona, Spain. 7. The Campus of International Excellence Southern Catalonia, Tarragona, Spain.
Abstract
BACKGROUND: Obesity can influence hepatic mitochondrial function, and cause non-alcoholic steatohepatitis (NASH). Diagnosis and follow-up rely on invasive liver biopsy so blood-based markers are urgently required. AIM: To investigate whether values of circulating metabolites from energy and one-carbon (1-C) metabolism may: (a) reflect hepatic mitochondrial flexibility failure and (b) act as NASH biomarkers. METHODS: Patients with severe obesity undergoing bariatric surgery (n = 270) were investigated using quantitative targeted plasma metabolomics. Comparisons were with non-obese controls without liver disease (n = 50). Obese patients with NASH (n = 53) and without NASH (n = 130) representing extreme groups of liver disease were assessed to test the diagnostic ability of the measured circulating metabolites. Paired liver biopsy and plasma samples from NASH patients were available 1 year post-surgery and were evaluated to monitor metabolomic changes with liver damage resolution. RESULTS: We identified correlations between human liver metabolism and obesity. High-plasma α-ketoglutarate (α-KG) and lactate concentrations in NASH patients indicating citric acid cycle replenishment via glutaminolysis might also be a crucial point in NASH onset. Plasma measurements of α-KG, β-hydroxybutyrate, pyruvate and oxaloacetate reduced the uncertainty in clinical diagnosis of NASH [area under receiver operating characteristic curve (AUC) of 0.826] and predicted NASH resolution without ambiguity (AUC of 0.999). CONCLUSION: Changes in plasma mitochondrial metabolites appear to be associated with NASH. These metabolic responses may be dynamically remodelled following resolution of liver damage through massive weight loss.
BACKGROUND:Obesity can influence hepatic mitochondrial function, and cause non-alcoholic steatohepatitis (NASH). Diagnosis and follow-up rely on invasive liver biopsy so blood-based markers are urgently required. AIM: To investigate whether values of circulating metabolites from energy and one-carbon (1-C) metabolism may: (a) reflect hepatic mitochondrial flexibility failure and (b) act as NASH biomarkers. METHODS:Patients with severe obesity undergoing bariatric surgery (n = 270) were investigated using quantitative targeted plasma metabolomics. Comparisons were with non-obese controls without liver disease (n = 50). Obese patients with NASH (n = 53) and without NASH (n = 130) representing extreme groups of liver disease were assessed to test the diagnostic ability of the measured circulating metabolites. Paired liver biopsy and plasma samples from NASHpatients were available 1 year post-surgery and were evaluated to monitor metabolomic changes with liver damage resolution. RESULTS: We identified correlations between human liver metabolism and obesity. High-plasma α-ketoglutarate (α-KG) and lactate concentrations in NASHpatients indicating citric acid cycle replenishment via glutaminolysis might also be a crucial point in NASH onset. Plasma measurements of α-KG, β-hydroxybutyrate, pyruvate and oxaloacetate reduced the uncertainty in clinical diagnosis of NASH [area under receiver operating characteristic curve (AUC) of 0.826] and predicted NASH resolution without ambiguity (AUC of 0.999). CONCLUSION: Changes in plasma mitochondrial metabolites appear to be associated with NASH. These metabolic responses may be dynamically remodelled following resolution of liver damage through massive weight loss.
Authors: Anna Hernández-Aguilera; Núria Casacuberta; Helena Castañé; Montserrat Fibla; Salvador Fernández-Arroyo; Isabel Fort-Gallifa; Marta París; Fàtima Sabench; Daniel Del Castillo; Gerard Baiges-Gaya; Elisabet Rodríguez-Tomàs; Teresa Sans; Jordi Camps; Jorge Joven Journal: Biol Trace Elem Res Date: 2021-02-08 Impact factor: 3.738
Authors: Noemí Cabré; Fedra Luciano-Mateo; Douglas J Chapski; Gerard Baiges-Gaya; Salvador Fernández-Arroyo; Anna Hernández-Aguilera; Helena Castañé; Elisabet Rodríguez-Tomàs; Marta París; Fàtima Sabench; Daniel Del Castillo; Josep M Del Bas; Mercedes Tomé; Clément Bodineau; Alejandro Sola-García; José López-Miranda; Alejandro Martín-Montalvo; Raúl V Durán; Thomas M Vondriska; Manuel Rosa-Garrido; Jordi Camps; Javier A Menéndez; Jorge Joven Journal: Int J Mol Sci Date: 2022-07-15 Impact factor: 6.208
Authors: Martin Pehrsson; Tina Manon-Jensen; Shu Sun; Ida F Villesen; Helena Castañé; Jorge Joven; Keyur Patel; Zachary Goodman; Mette J Nielsen; Anne-Christine Bay-Jensen; Diana J Leeming; Joachim H Mortensen; Morten A Karsdal Journal: Liver Int Date: 2022-04-12 Impact factor: 8.754