1. Antagonic effect of ghrelin and LEAP-2 on hepatic stellate cell activation and liver fibrosis in obesity-associated nonalcoholic fatty liver disease.
- Author
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Ezquerro S, Tuero C, Becerril S, Valentí V, Moncada R, Landecho MF, Catalán V, Gómez-Ambrosi J, Mocha F, Silva C, Hanley KP, Escalada J, Frühbeck G, and Rodríguez A
- Subjects
- Humans, Transforming Growth Factor beta1 adverse effects, Transforming Growth Factor beta1 metabolism, Hepatic Stellate Cells metabolism, Hepatic Stellate Cells pathology, Phosphatidylinositol 3-Kinases metabolism, Phosphatidylinositol 3-Kinases pharmacology, Ghrelin adverse effects, Receptors, Ghrelin, Liver Cirrhosis etiology, Liver metabolism, Non-alcoholic Fatty Liver Disease metabolism, Obesity, Morbid
- Abstract
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.)
- Published
- 2023
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