Abstract | 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: 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.
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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 | Journal of hepatology
(J Hepatol)
(May 04 2021)
ISSN: 1600-0641 [Electronic] Netherlands |
PMID | 33961941
(Publication Type: Journal Article)
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Copyright | Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved. |