期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 23, 期 14, 页码 -出版社
MDPI
DOI: 10.3390/ijms23147830
关键词
bariatric surgery; DNA methylation; energy metabolism; epigenetics; functional studies; glutaminolysis; multi-omics approach
资金
- Instituto de Salud Carlos III, Madrid, Spain [PI15/00285, PI18/00921, PI18/01590, CPII/00023]
- European Regional Development Fund [FEDER]
- Generalitat de Catalunya, Barcelona, Spain [SGR1227]
- Fundacio La Marato de TV3, Barcelona, Spain [60/U/2016]
- Ministry of Science, Innovation and Universities, Madrid, Spain [PGC2018-096244-B-I00]
The study investigates the signaling processes involved in the development of nonalcoholic steatohepatitis using a surgically induced remission model of liver disease. The results suggest that surgery can decrease the inflammatory response and reveal the role of mitogen-activated protein kinases. Furthermore, increased glutaminolysis-induced production of alpha-ketoglutarate and dysregulation of mammalian target of rapamycin complex 1 play a crucial role in the inefficient adaptive responses leading to steatohepatitis in obesity.
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 alpha-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 alpha-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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据