Multi-omics profiling reveals altered mitochondrial metabolism in adipose tissue from patients with metabolic dysfunction-associated steatohepatitisResearch in context
Helena Castañé,
Andrea Jiménez-Franco,
Anna Hernández-Aguilera,
Cristian Martínez-Navidad,
Vicente Cambra-Cortés,
Alina-Iuliana Onoiu,
Juan Manuel Jiménez-Aguilar,
Marta París,
Mercè Hernández,
David Parada,
Carmen Guilarte,
Antonio Zorzano,
María Isabel Hernández-Alvarez,
Jordi Camps,
Jorge Joven
Affiliations
Helena Castañé
Unitat de Recerca Biomèdica, Hospital Universitari de Sant Joan, Universitat Rovira i Virgili, Institut d’Investigació Sanitària Pere Virgili, Reus, Spain; Department of Medicine and Surgery, Faculty of Medicine, Universitat Rovira i Virgili, Reus, Spain; Corresponding authors. Unitat de Recerca Biomèdica, Hospital Universitari Sant Joan, Universitat Rovira i Virgili, Institut d’Investigació Sanitària Pere Virgili, Av. Doctor Laporte, 2, Reus, Tarragona 43204, Spain.
Andrea Jiménez-Franco
Unitat de Recerca Biomèdica, Hospital Universitari de Sant Joan, Universitat Rovira i Virgili, Institut d’Investigació Sanitària Pere Virgili, Reus, Spain; Department of Medicine and Surgery, Faculty of Medicine, Universitat Rovira i Virgili, Reus, Spain
Anna Hernández-Aguilera
Department of Pathology, Hospital Universitari de Sant Joan, Reus, Spain
Cristian Martínez-Navidad
Unitat de Recerca Biomèdica, Hospital Universitari de Sant Joan, Universitat Rovira i Virgili, Institut d’Investigació Sanitària Pere Virgili, Reus, Spain
Vicente Cambra-Cortés
Unitat de Recerca Biomèdica, Hospital Universitari de Sant Joan, Universitat Rovira i Virgili, Institut d’Investigació Sanitària Pere Virgili, Reus, Spain
Alina-Iuliana Onoiu
Unitat de Recerca Biomèdica, Hospital Universitari de Sant Joan, Universitat Rovira i Virgili, Institut d’Investigació Sanitària Pere Virgili, Reus, Spain
Juan Manuel Jiménez-Aguilar
Unitat de Recerca Biomèdica, Hospital Universitari de Sant Joan, Universitat Rovira i Virgili, Institut d’Investigació Sanitària Pere Virgili, Reus, Spain
Marta París
Unitat de Recerca Biomèdica, Hospital Universitari de Sant Joan, Universitat Rovira i Virgili, Institut d’Investigació Sanitària Pere Virgili, Reus, Spain; Department of Surgery, Hospital Universitari de Sant Joan, Reus, Spain
Mercè Hernández
Unitat de Recerca Biomèdica, Hospital Universitari de Sant Joan, Universitat Rovira i Virgili, Institut d’Investigació Sanitària Pere Virgili, Reus, Spain; Department of Surgery, Hospital Universitari de Sant Joan, Reus, Spain
David Parada
Department of Pathology, Hospital Universitari de Sant Joan, Reus, Spain
Carmen Guilarte
Department of Pathology, Hospital Universitari de Sant Joan, Reus, Spain
Antonio Zorzano
Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Universitat de Barcelona, Barcelona, Spain; Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
María Isabel Hernández-Alvarez
Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Universitat de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain; Institut de Biomedicina de la Universitat de Barcelona IBUB, Barcelona, Spain
Jordi Camps
Unitat de Recerca Biomèdica, Hospital Universitari de Sant Joan, Universitat Rovira i Virgili, Institut d’Investigació Sanitària Pere Virgili, Reus, Spain; Department of Medicine and Surgery, Faculty of Medicine, Universitat Rovira i Virgili, Reus, Spain; Corresponding author. Unitat de Recerca Biomèdica, Hospital Universitari Sant Joan, Universitat Rovira i Virgili, Institut d’Investigació Sanitària Pere Virgili, Av. Doctor Laporte, 2, Reus, Tarragona 43204, Spain.
Jorge Joven
Unitat de Recerca Biomèdica, Hospital Universitari de Sant Joan, Universitat Rovira i Virgili, Institut d’Investigació Sanitària Pere Virgili, Reus, Spain; Department of Medicine and Surgery, Faculty of Medicine, Universitat Rovira i Virgili, Reus, Spain; The Campus of International Excellence Southern Catalonia, Tarragona, Spain; Corresponding author. Unitat de Recerca Biomèdica, Hospital Universitari Sant Joan, Universitat Rovira i Virgili, Institut d’Investigació Sanitària Pere Virgili, Av. Doctor Laporte, 2, Reus, Tarragona 43204, Spain.
Summary: Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) and its more severe form steatohepatitis (MASH) contribute to rising morbidity and mortality rates. The storage of fat in humans is closely associated with these diseases’ progression. Thus, adipose tissue metabolic homeostasis could be key in both the onset and progression of MASH. Methods: We conducted a case-control observational research using a systems biology-based approach to analyse liver, abdominal subcutaneous adipose tissue (SAT), omental visceral adipose tissue (VAT), and blood of n = 100 patients undergoing bariatric surgery (NCT05554224). MASH was diagnosed through histologic assessment. Whole-slide image analysis, lipidomics, proteomics, and transcriptomics were performed on tissue samples. Lipidomics and proteomics profiles were determined on plasma samples. Findings: Liver transcriptomics, proteomics, and lipidomics revealed interconnected pathways associated with inflammation, mitochondrial dysfunction, and lipotoxicity in MASH. Paired adipose tissue biopsies had larger adipocyte areas in both fat depots in MASH. Enrichment analyses of proteomics and lipidomics data confirmed the association of liver lesions with mitochondrial dysfunction in VAT. Plasma lipidomics identified candidates with high diagnostic accuracy (AUC = 0.919, 95% CI 0.840–0.979) for screening MASH. Interpretation: Mitochondrial dysfunction is also present in VAT in patients with obesity-associated MASH. This may cause a disruption in the metabolic equilibrium of lipid processing and storage, which impacts the liver and accelerates detrimental adaptative responses. Funding: The project leading to these results has received funding from ‘la Caixa' Foundation (HR21-00430), and from the Instituto de Salud Carlos III (ISCIII) (PI21/00510) and co-funded by the European Union.
