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GLP-1 and GIP agonism has no direct actions in human hepatocytes or hepatic stellate cells.
Cell. Mol. Life Sci. 81:468 (2024)
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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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
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
Volume: 81,
Issue: 1,
Article Number: 468
Publisher
Birkhäuser
Publishing Place
Picassoplatz 4, Basel, 4052, Switzerland
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Institute of Diabetes and Obesity (IDO)
Grants
Ministerio de Ciencia e Innovacin