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Da Silva Lima, N.* ; Cabaleiro, A.* ; Novoa, E.* ; Riobello, C.* ; Knerr, P.J.* ; He, Y.* ; Esquinas-Román, E.M.* ; González-García, I.* ; Prévot, V.* ; Schwaninger, M.* ; Dieguez, C.* ; López, M.* ; Müller, T.D. ; Varela-Rey, M.* ; Douros, J.D.* ; Nogueiras, R.*

GLP-1 and GIP agonism has no direct actions in human hepatocytes or hepatic stellate cells.

Cell. Mol. Life Sci. 81:468 (2024)
Verlagsversion DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
The use of incretin agonists for managing metabolic dysfunction-associated steatohepatitis (MASH) is currently experiencing considerable interest. However, whether these compounds have a direct action on MASH is still under debate. This study aims to investigate whether GLP-1R/GIPR agonists act directly in hepatocytes and hepatic stellate cells (HSCs). For this, human hepatocyte and HSCs lines, as well as primary human hepatocytes and HSCs treated with Liraglutide, Acyl-GIP or the GLP-1/GIP dual agonist (MAR709) were used. We show that the concentrations of each compound, which were effective in insulin release, did not induce discernible alterations in either hepatocytes or HSCs. In hepatocytes displaying elevated fatty acid content after the treatment with oleic acid and palmitic acid, none of the three compounds reduced lipid concentration. Similarly, in HSCs activated with transforming growth factor-β (TGFb), Liraglutide, Acyl-GIP and MAR709 failed to ameliorate the elevated expression of fibrotic markers. The three compounds were also ineffective in phosphorylating CREB, which mediates insulinotropic actions, in both hepatocytes and HSCs. These findings indicate that incretin agonists have no direct actions in human hepatocytes or hepatic stellate cells, suggesting that their beneficial effects in patients with MASH are likely mediated indirectly, potentially through improvements in body weight, insulin resistance and glycemic control.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Fatty Acids ; Gipr ; Glp-1r ; Liver Fibrosis; Inhibitory Polypeptide Receptor; Insulin-resistance; Weight-loss; High-fat; Expression; Glucagon; Disturbances; Fibrosis; Obesity; Mice
ISSN (print) / ISBN 1420-682X
e-ISSN 1420-9071
Quellenangaben Band: 81, Heft: 1, Seiten: , Artikelnummer: 468 Supplement: ,
Verlag Birkhäuser
Verlagsort Picassoplatz 4, Basel, 4052, Switzerland
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Förderungen Ministerio de Ciencia e Innovacin