Glutaminolysis-induced mTORC1 activation drives non-alcoholic steatohepatitis progression.

Autor: Cabré N; Universitat Rovira i Virgili, Department of Medicine and Surgery, Reus, Spain; Unitat de Recerca Biomèdica (URB-CRB), Hospital Universitari de Sant Joan, Institut d'Investigacio Sanitaria Pere Virgili, Universitat Rovira i Virgili, Reus, Spain., Luciano-Mateo F; Universitat Rovira i Virgili, Department of Medicine and Surgery, Reus, Spain; Unitat de Recerca Biomèdica (URB-CRB), Hospital Universitari de Sant Joan, Institut d'Investigacio Sanitaria Pere Virgili, Universitat Rovira i Virgili, Reus, Spain., Chapski DJ; Department of Anesthesiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, US., Baiges-Gaya G; Universitat Rovira i Virgili, Department of Medicine and Surgery, Reus, Spain; Unitat de Recerca Biomèdica (URB-CRB), Hospital Universitari de Sant Joan, Institut d'Investigacio Sanitaria Pere Virgili, Universitat Rovira i Virgili, Reus, Spain., Fernández-Arroyo S; Universitat Rovira i Virgili, Department of Medicine and Surgery, Reus, Spain; Unitat de Recerca Biomèdica (URB-CRB), Hospital Universitari de Sant Joan, Institut d'Investigacio Sanitaria Pere Virgili, Universitat Rovira i Virgili, Reus, Spain., Hernández-Aguilera A; Universitat Rovira i Virgili, Department of Medicine and Surgery, Reus, Spain; Unitat de Recerca Biomèdica (URB-CRB), Hospital Universitari de Sant Joan, Institut d'Investigacio Sanitaria Pere Virgili, Universitat Rovira i Virgili, Reus, Spain., Castañé H; Universitat Rovira i Virgili, Department of Medicine and Surgery, Reus, Spain; Unitat de Recerca Biomèdica (URB-CRB), Hospital Universitari de Sant Joan, Institut d'Investigacio Sanitaria Pere Virgili, Universitat Rovira i Virgili, Reus, Spain., Rodríguez-Tomàs E; Universitat Rovira i Virgili, Department of Medicine and Surgery, Reus, Spain; Unitat de Recerca Biomèdica (URB-CRB), Hospital Universitari de Sant Joan, Institut d'Investigacio Sanitaria Pere Virgili, Universitat Rovira i Virgili, Reus, Spain., París M; Department of Surgery, Hospital Universitari de Sant Joan, Institut d'Investigació Sanitaria Pere Virgili, Universitat Rovira i Virgili, Reus, Spain., Sabench F; Department of Surgery, Hospital Universitari de Sant Joan, Institut d'Investigació Sanitaria Pere Virgili, Universitat Rovira i Virgili, Reus, Spain., Del Castillo D; Department of Surgery, Hospital Universitari de Sant Joan, Institut d'Investigació Sanitaria Pere Virgili, Universitat Rovira i Virgili, Reus, Spain., Del Bas JM; Technological Unit of Nutrition and Health, EURECAT-Technology Centre of Catalonia, Reus, Spain., Tomé M; Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Consejo Superior de Investigaciones Científicas - Universidad Pablo de Olavide, Avda. Américo Vespucio 24, 41092 Sevilla, Spain., Bodineau C; Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Consejo Superior de Investigaciones Científicas - Universidad Pablo de Olavide, Avda. Américo Vespucio 24, 41092 Sevilla, Spain; Institut Européen de Chimie et Biologie, INSERM U1218, Université de Bordeaux, 2 Rue Robert Escarpit, Pessac 33607, France., Sola-García A; Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Consejo Superior de Investigaciones Científicas - Universidad Pablo de Olavide, Avda. Américo Vespucio 24, 41092 Sevilla, Spain., López-Miranda J; Lipids and Atherosclerosis Unit, IMIBIC/Reina Sofia University Hospital. University of Cordoba, Cordoba, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Cordoba, Spain., Martín-Montalvo A; Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Consejo Superior de Investigaciones Científicas - Universidad Pablo de Olavide, Avda. Américo Vespucio 24, 41092 Sevilla, Spain., Durán RV; Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Consejo Superior de Investigaciones Científicas - Universidad Pablo de Olavide, Avda. Américo Vespucio 24, 41092 Sevilla, Spain; Institut Européen de Chimie et Biologie, INSERM U1218, Université de Bordeaux, 2 Rue Robert Escarpit, Pessac 33607, France., Vondriska TM; Department of Anesthesiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, US., Rosa-Garrido M; Department of Anesthesiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, US., Camps J; Universitat Rovira i Virgili, Department of Medicine and Surgery, Reus, Spain; Unitat de Recerca Biomèdica (URB-CRB), Hospital Universitari de Sant Joan, Institut d'Investigacio Sanitaria Pere Virgili, Universitat Rovira i Virgili, Reus, Spain. Electronic address: jcamps@grupsagessa.com., Menéndez JA; Program Against Cancer Therapeutic Resistance (ProCURE), Metabolism and Cancer Group , Catalan Institute of Oncology, Girona , Spain; Girona Biomedical Research Institute (IDIBGI), Girona, Spain., Joven J; Universitat Rovira i Virgili, Department of Medicine and Surgery, Reus, Spain; Unitat de Recerca Biomèdica (URB-CRB), Hospital Universitari de Sant Joan, Institut d'Investigacio Sanitaria Pere Virgili, Universitat Rovira i Virgili, Reus, Spain; The Campus of International Excellence Southern Catalonia, Tarragona, Spain. Electronic address: jorge.joven@urv.cat.
Jazyk: angličtina
Zdroj: Journal of hepatology [J Hepatol] 2021 May 04. Date of Electronic Publication: 2021 May 04.
DOI: 10.1016/j.jhep.2021.04.037
Abstrakt: Background & Aims: A holistic insight on the relationship between obesity and metabolic dysfunction-associated fatty liver disease is an unmet clinical need. Omics investigations can be used to investigate the multifaceted role of altered mitochondrial pathways to promote nonalcoholic steatohepatitis, a major risk factor for liver disease-associated death. There are no specific treatments but remission via surgery might offer an opportunity to examine the signaling processes that govern the complex spectrum of chronic liver diseases observed in extreme obesity. We aim to assess the emerging relationship between metabolism, methylation and liver disease.
Methods: We tailed the flow of information, before and after steatohepatitis remission, from biochemical, histological, and multi-omics analyses in liver biopsies from patients with extreme obesity and successful bariatric surgery. Functional studies were performed in HepG2 cells and primary hepatocytes.
Results: The reversal of hepatic mitochondrial dysfunction and the control of oxidative stress and inflammatory responses revealed the regulatory role of mitogen-activated protein kinases. The reversible metabolic rearrangements leading to steatohepatitis increased the glutaminolysis-induced production of α-ketoglutarate and the hyperactivation of mammalian target of rapamycin complex 1. These changes were crucial for the adenosine monophosphate-activated protein kinase/mammalian target of rapamycin-driven pathways that modulated hepatocyte survival by coordinating apoptosis and autophagy. The signaling activity of α-ketoglutarate and the associated metabolites also affected methylation-related epigenomic remodeling enzymes. Integrative analysis of hepatic transcriptome signatures and differentially methylated genomic regions distinguished patients with and without steatohepatitis.
Conclusion: We provide evidence supporting the multifaceted potential of the increased glutaminolysis-induced α-ketoglutarate production and the mammalian target of rapamycin complex 1 dysregulation as a conceivable source of the inefficient adaptive responses leading to steatohepatitis.
Lay Summary: Steatohepatitis is a frequent and threatening complication of extreme obesity without specific treatment. Omics technologies can be used to identify therapeutic targets. We highlight increased glutaminolysis-induced α-ketoglutarate production as a potential source of signals promoting and exacerbating steatohepatitis.
(Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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