RT Journal Article
T1 Ghrelin Reduces TNF-α-Induced Human Hepatocyte Apoptosis, Autophagy, and Pyroptosis: Role in Obesity-Associated NAFLD.
A1 Ezquerro, Silvia
A1 Mocha, Fatima
A1 Fruhbeck, Gema
A1 Guzman-Ruiz, Rocio
A1 Valenti, Victor
A1 Mugueta, Carmen
A1 Becerril, Sara
A1 Catalan, Victoria
A1 Gomez-Ambrosi, Javier
A1 Silva, Camilo
A1 Salvador, Javier
A1 Colina, Inmaculada
A1 Malagon, Maria M
A1 Rodriguez, Amaia
AB Human obesity is associated with increased circulating TNF-α, a proinflammatory cytokine that induces hepatocyte cell death. The potential beneficial effects of acylated and desacyl ghrelin in the progression of nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis in obesity via the inhibition of TNF-α-induced hepatocyte apoptosis, autophagic cell death, and pyroptosis were investigated. Plasma ghrelin isoforms and TNF-α were measured in 158 participants, and hepatocyte cell death was evaluated in liver biopsies from 76 patients with morbid obesity undergoing bariatric surgery with available liver echography and pathology analysis. The effect of acylated and desacyl ghrelin on basal and TNF-α-induced cell death was determined in vitro in human HepG2 hepatocytes. Circulating TNF-α and the acylated/desacyl ghrelin ratio were increased, whereas desacyl ghrelin levels were decreased in patients with obesity and NAFLD. Six months after bariatric surgery, decreased acylated/desacyl ghrelin levels, and improved hepatic function were found. Patients with obesity and type 2 diabetes showed increased hepatic ghrelin O-acyltransferase transcripts as well as an increased hepatic apoptosis, pyroptosis, and compromised autophagy. In HepG2 hepatocytes, acylated and desacyl ghrelin treatment reduced TNF-α-induced apoptosis, evidenced by lower caspase-8 and caspase-3 cleavage, as well as TUNEL-positive cells and pyroptosis, revealed by decreased caspase-1 activation and lower high-mobility group box 1 expression. Moreover, acylated ghrelin suppressed TNF-α-activated hepatocyte autophagy, as evidenced by a decreased LC3B-II/I ratio and increased p62 accumulation via AMPK/mTOR. Ghrelin constitutes a protective factor against hepatocyte cell death. The increased acylated/desacyl ghrelin ratio in patients with obesity and NAFLD might constitute a compensatory mechanism to overcome TNF-α-induced hepatocyte apoptosis, autophagy, and pyroptosis.
PB Oxford University Press
YR 2018
FD 2018-08-15
LK http://hdl.handle.net/10668/12867
UL http://hdl.handle.net/10668/12867
LA en
NO Ezquerro S, Mocha F, Frühbeck G, Guzmán-Ruiz R, Valentí V, Mugueta C, et al. Ghrelin Reduces TNF-α-Induced Human Hepatocyte Apoptosis, Autophagy, and Pyroptosis: Role in Obesity-Associated NAFLD. J Clin Endocrinol Metab. 2019 Jan 1;104(1):21-37
NO We gratefully acknowledge the valuable collaboration of the Departments of Surgery and Anesthesia and the Nutrition Unit of the Clínica Universidad de Navarra. We are indebted to Dr.José Manuel Fernández-Real (Institut d’Investigación Biomédica de Girona, Girona, Spain) for providing the MCM-LPS 5%. We also thank Andrés Trávez (Instituto Maimónides de Investigaci ón Biomédica de Córdoba, University of Córdoba, Spain) for technical assistance in the confocal studies. Financial Support: This work was supported by Fondo de Investigación Sanitaria-FEDER [FIS PI13/01430 (to A.R.), PI16/00221 (to A.R.), and PI16/01217 (to G.F.)] from the Institutode Salud Carlos III and MINECO-FEDER [BFU-2015-70454-REDT (to M.M.M.) and BFU2016-76711-R (to M.M.M.)]. CIBEROBN is an initiative of the Instituto de Salud Carlos III, Spain.
DS RISalud
RD Apr 7, 2025