GLP-1 and GIP agonism has no direct actions in human hepatocytes or hepatic stellate cells
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.
Authors
- Jonathan D. Douros (ORCID: https://orcid.org/0000-0003-2299-6163)
- Markus Schwaninger (ORCID: https://orcid.org/0000-0002-4510-9718)
- Natália da Silva Lima (ORCID: https://orcid.org/0000-0001-9448-4090)
- Rubén Nogueiras (ORCID: https://orcid.org/0000-0002-9976-9930)
- Patrick J. Knerr
- Ismael González‐García (ORCID: https://orcid.org/0000-0002-5545-5841)
- Carlos Diéguez (ORCID: https://orcid.org/0000-0002-0919-4337)
- Marta Varela‐Rey (ORCID: https://orcid.org/0000-0002-2413-8659)
- Timo D. Müller (ORCID: https://orcid.org/0000-0002-0624-9339)
- Alba Cabaleiro
- Cristina Riobello (ORCID: https://orcid.org/0000-0002-8854-6854)
- Vincent Prévot (ORCID: https://orcid.org/0000-0001-7185-3615)
- Eva M. Esquinas-Román (ORCID: https://orcid.org/0000-0002-6412-1405)
- Miguel López (ORCID: https://orcid.org/0000-0002-7823-1648)
- Yantao He (ORCID: https://orcid.org/0000-0002-2692-0345)
- Eva Nóvoa (ORCID: https://orcid.org/0000-0002-6708-5382)
Institutions
- Inserm (FR)
- Universidade de Santiago de Compostela (ES)
- Université de Lille (FR)
- Xunta de Galicia (ES)
- Instituto de Salud Carlos III (ES)
- Indiana Biosciences Research Institute (US)
- Helmholtz Zentrum München (DE)
- Centre Hospitalier Universitaire de Lille (FR)
- Novo Nordisk (United States) (US)
- Center for Research in Molecular Medicine and Chronic Diseases (ES)
- Centro de Investigación Biomédica en Red (ES)
- Deutsches Diabetes-Zentrum e.V. (DE)
- German Center for Diabetes Research (DE)
- European Genomic Institute for Diabetes (FR)
- Heinrich Heine University Düsseldorf (DE)
- Ludwig-Maximilians-Universität München (DE)
- University of Lübeck (DE)
Publication Details
- Journal
- Cellular and Molecular Life Sciences
- Published
- 2024-11-28
- DOI
- https://doi.org/10.1007/s00018-024-05507-6
- Citations
- 17
- Primary Topic
- Liver Disease Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 6.57
Funders
- Ministerio de Ciencia e Innovación
- Consellería de Cultura, Educación e Ordenación Universitaria, Xunta de Galicia
- European Research Council