Scientific publications

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

Jul 10, 2023 | Magazine: European Journal of Endocrinology

Silvia Ezquerro  1 , Carlota Tuero  2 , Sara Becerril  1   3   4 , Víctor Valentí  2   3   4 , Rafael Moncada  2   3   5 , Manuel F Landecho  6 , Victoria Catalán  1   3   4 , Javier Gómez-Ambrosi  1   3   4 , Fátima Mocha  1 , Camilo Silva  3   4   7 , Karen Piper Hanley  8 , Javier Escalada  3   4   7 , Gema Frühbeck  1   3   4   7 , Amaia Rodríguez  1   3   4

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.

CITATION  Eur J Endocrinol. 2023 Jul 10;188(7):564-577. doi: 10.1093/ejendo/lvad071