Antagonic effect of ghrelin and LEAP-2 on hepatic stellate cell activation and liver fibrosis in obesity-associated nonalcoholic fatty liver disease.

Autor:	Ezquerro S; Metabolic Research Laboratory, Clínica Universidad de Navarra, 31008 Pamplona, Spain., Tuero C; Department of Surgery, Clínica Universidad de Navarra, 31008 Pamplona, Spain., Becerril S; Metabolic Research Laboratory, Clínica Universidad de Navarra, 31008 Pamplona, Spain.; CIBEROBN, Instituto de Salud Carlos III, 28029 Madrid, Spain.; Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), 31008 Pamplona, Spain., Valentí V; Department of Surgery, Clínica Universidad de Navarra, 31008 Pamplona, Spain.; CIBEROBN, Instituto de Salud Carlos III, 28029 Madrid, Spain.; Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), 31008 Pamplona, Spain., Moncada R; Department of Surgery, Clínica Universidad de Navarra, 31008 Pamplona, Spain.; CIBEROBN, Instituto de Salud Carlos III, 28029 Madrid, Spain.; Department of Anesthesia, Clínica Universidad de Navarra, 31008 Pamplona, Spain., Landecho MF; Department of Internal Medicine, Clínica Universidad de Navarra, 31008 Pamplona, Spain., Catalán V; Metabolic Research Laboratory, Clínica Universidad de Navarra, 31008 Pamplona, Spain.; CIBEROBN, Instituto de Salud Carlos III, 28029 Madrid, Spain.; Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), 31008 Pamplona, Spain., Gómez-Ambrosi J; Metabolic Research Laboratory, Clínica Universidad de Navarra, 31008 Pamplona, Spain.; CIBEROBN, Instituto de Salud Carlos III, 28029 Madrid, Spain.; Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), 31008 Pamplona, Spain., Mocha F; Metabolic Research Laboratory, Clínica Universidad de Navarra, 31008 Pamplona, Spain., Silva C; CIBEROBN, Instituto de Salud Carlos III, 28029 Madrid, Spain.; Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), 31008 Pamplona, Spain.; Department of Endocrinology & Nutrition, Clínica Universidad de Navarra, 31008 Pamplona, Spain., Hanley KP; Division of Diabetes, Endocrinology and Gastroenterology, Wellcome Trust Centre for Cell-Matrix Research, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester, M13 9PT, United Kingdom., Escalada J; CIBEROBN, Instituto de Salud Carlos III, 28029 Madrid, Spain.; Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), 31008 Pamplona, Spain.; Department of Endocrinology & Nutrition, Clínica Universidad de Navarra, 31008 Pamplona, Spain., Frühbeck G; Metabolic Research Laboratory, Clínica Universidad de Navarra, 31008 Pamplona, Spain.; CIBEROBN, Instituto de Salud Carlos III, 28029 Madrid, Spain.; Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), 31008 Pamplona, Spain.; Department of Endocrinology & Nutrition, Clínica Universidad de Navarra, 31008 Pamplona, Spain., Rodríguez A; Metabolic Research Laboratory, Clínica Universidad de Navarra, 31008 Pamplona, Spain.; CIBEROBN, Instituto de Salud Carlos III, 28029 Madrid, Spain.; Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), 31008 Pamplona, Spain.
Jazyk:	angličtina
Zdroj:	European journal of endocrinology [Eur J Endocrinol] 2023 Jul 10; Vol. 188 (7), pp. 564-577.
DOI:	10.1093/ejendo/lvad071
Abstrakt:	Background: Growing evidence suggests the key role of ghrelin in the onset and progression of nonalcoholic fatty liver disease (NAFLD). The potential participation of ghrelin and the ghrelin receptor antagonist, LEAP-2, in the onset of liver fibrosis in patients with severe obesity and NAFLD through the regulation of TGF-β1-induced hepatic stellate cell (HSC) activation was investigated. Methods: Circulating (n = 179) and hepatic expression (n = 95) of ghrelin and LEAP-2 were measured in patients with severe obesity and available liver pathology analysis undergoing Roux-en-Y gastric bypass (RYGB). The effect of ghrelin isoforms and LEAP-2 on TGF-β1-induced HSC activation, fibrogenic response, and contractile properties was evaluated in vitro in human LX-2 cells. Results: Plasma and hepatic ghrelin were negatively associated, while LEAP-2 exhibited a positive association with liver fibrosis in patients with obesity and NAFLD. Six months after RYGB, hepatic function was improved and, although acylated ghrelin and LEAP-2 concentrations remained unchanged, both hormones were inversely related to post-surgical levels of profibrogenic factors TGF-β1 and TIMP-1. Acylated ghrelin treatment reversed TGF-β1-induced myofibroblast-like phenotype, collagen contractile properties, and the upregulation of factors involved in HSC activation and fibrogenesis via PI3K/Akt/mTOR pathway. Moreover, acylated ghrelin inhibited the mild HSC activation induced by LEAP-2. Conclusions: Ghrelin is an anti-fibrogenic factor blocking HSC activation induced by the most potent fibrogenic cytokine, TGF-β1, and LEAP-2. The imbalance between acylated ghrelin and ghrelin receptor antagonist LEAP-2 might contribute to maintain liver fibrosis in patients with obesity and NAFLD. (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Endocrinology.)
Databáze:	MEDLINE
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