Laparoscopic Sleeve Gastrectomy in Patients with Severe Obesity Restores Adaptive Responses Leading to Nonalcoholic Steatohepatitis
| Autor: | 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 |
|---|---|
| Přispěvatelé: | Instituto de Salud Carlos III, European Commission, Generalitat de Catalunya, Fundació La Marató de TV3, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España) |
| Rok vydání: | 2022 |
| Předmět: |
glutaminolysis
bariatric surgery Chronic Liver Disease and Cirrhosis Catalysis Oral and gastrointestinal Hepatitis Inorganic Chemistry Functional studies Gastrectomy Non-alcoholic Fatty Liver Disease Clinical Research energy metabolism Genetics Humans 2.1 Biological and endogenous factors Obesity Physical and Theoretical Chemistry Morbid Aetiology Molecular Biology Glutaminolysis Spectroscopy Bariatric surgery DNA methylation Chemical Physics epigenetics TOR Serine-Threonine Kinases Liver Disease functional studies multi-omics approach Organic Chemistry Human Genome Energy metabolism General Medicine Multi-omics approach Obesity Morbid Computer Science Applications Ketoglutaric Acids Epigenetics Laparoscopy Other Biological Sciences Digestive Diseases Other Chemical Sciences Biotechnology |
| Zdroj: | International journal of molecular sciences, vol 23, iss 14 International Journal of Molecular Sciences; Volume 23; Issue 14; Pages: 7830 |
| Popis: | The surgically induced remission of liver disease represents a model to investigate the signalling processes that trigger the development of nonalcoholic steatohepatitis with the aim of identifying novel therapeutic targets. We recruited patients with severe obesity with or without nonalcoholic steatohepatitis and obtained liver and plasma samples before and after laparoscopic sleeve gastrectomy for immunoblotting, immunocytochemical, metabolomic, transcriptomic and epigenetic analyses. Functional studies were performed in HepG2 cells and primary hepatocytes. Surgery was associated with a decrease in the inflammatory response and revealed the role of mitogen-activated protein kinases. Nonalcoholic steatohepatitis was associated with an increased glutaminolysis-induced production of α-ketoglutarate and the hyperactivation of mammalian target of rapamycin complex 1. These changes were crucial for adenosine monophosphate-activated protein kinase/mammalian target of rapamycin-driven pathways that modulated hepatocyte survival by coordinating apoptosis and autophagy and affected methylation-related epigenomic remodelling enzymes. Hepatic transcriptome signatures and differentially methylated genomic regions distinguished patients with and without steatohepatitis. Our results suggest that the increased glutaminolysis-induced α-ketoglutarate production and the mammalian target of rapamycin complex 1 dysregulation play a crucial role in the inefficient adaptive responses leading to steatohepatitis in obesity. This study was funded by Instituto de Salud Carlos III, Madrid, Spain (Grants PI15/00285, PI18/00921, PI18/01590, and CPII/00023) co-funded by the European Regional Development Fund [FEDER], the Generalitat de Catalunya, Barcelona, Spain (SGR1227), Fundació La Marató de TV3, Barcelona, Spain (60/U/2016), and Ministry of Science, Innovation and Universities, Madrid, Spain (PGC2018-096244-B-I00). |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|