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Article

Semaglutide Modulates Extracellular Matrix Production of LX-2 Cells via Exosomes and Improves Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)

by
Maria Principia Scavo
1,*,
Giuseppe Lisco
2,
Nicoletta Depalo
3,
Federica Rizzi
3,
Sara Volpe
2,
Valentina Arrè
1,
Livianna Carrieri
1,
Maria Notarnicola
4,
Valentina De Nunzio
4,
Maria Lucia Curri
5,
Giovanni De Pergola
6,
Giuseppina Piazzolla
2,† and
Gianluigi Giannelli
7,†
1
Laboratory of Personalized Medicine, National Institute of Gastroenterology, IRCCS DeBellis, 70013 Castellana Grotte, BA, Italy
2
Interdisciplinary Department of Medicine, School of Medicine, University of Bari “Aldo Moro”, Piazza Giulio Cesare 11, 70124 Bari, BA, Italy
3
Institute for Chemical-Physical Processes, Italian National Research Council (IPCF)-CNR SS Bari, Via Orabona 4, 70125 Bari, BA, Italy
4
Laboratory of Nutritional Biochemistry, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, BA, Italy
5
Dipartimento di Chimica, Università degli Studi di Bari Aldo Moro, Via Orabona 4, 70125 Bari, BA, Italy
6
Center of Nutrition for the Research and the Care of Obesity and Metabolic Diseases, National Institute of Gastroenterology IRCCS “Saverio de Bellis”, 70013 Castellana Grotte, BA, Italy
7
Scientific Direction, National Institute of Gastroenterology IRCCS “De Bellis,” Via Turi 27, 70013 Castellana Grotte, BA, Italy
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Int. J. Mol. Sci. 2024, 25(3), 1493; https://doi.org/10.3390/ijms25031493
Submission received: 18 December 2023 / Revised: 17 January 2024 / Accepted: 23 January 2024 / Published: 25 January 2024
(This article belongs to the Special Issue Understanding Metabolic Cross-Talk in Health and Disease)
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Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely related to some metabolic disorders, such as central obesity and type 2 diabetes (T2D). Glucagon-like peptide 1 receptor agonists (GLP-1RAs), such as semaglutide, may have therapeutic roles in MASLD associated with T2D. This study aims to investigate the molecular mechanisms underlying the effectiveness of semaglutide on MASLD in terms of progression from liver steatosis to fibrosis. We characterized exosomes from ten patients with type 2 diabetes (T2D) before (T0) and after 12 months (T12) of treatment with once-weekly subcutaneous semaglutide. Six of ten patients were considered responders to therapy (R) based on MASLD severity downgrading by at least one class according to a validated ultrasonographic (US) score. Normal hepatocytes (HEPA-RG) and stellate (LX-2) cells were challenged with exosomes from R and NR patients, isolated before and after 12 months of therapy. Exosomes from both R and NR patients isolated at T0 significantly affected LX-2 viability. After 12 months of treatment, only those isolated from R patients restored cell viability, whereas those from NR patients did not. No effects were observed on HEPA-RG cells. Exosomes at T12 from R but not from NR patients significantly decreased the production of α-SMA, a marker of LX-2 activation, a liver stellate cell model, and ph-SMAD2 and CTGF, involved in fibrosis processes. TGF-β1 was not modulated by the exosomes of R and NR patients. As a downstream effect, Vimentin, Collagen 1A1, and Fibronectin extracellular matrix components were also downregulated, as measured by droplets digital PCR. In conclusion, these results shed light on the potential effectiveness of semaglutide in improving liver fibrosis in MASLD.
Keywords: metabolic dysfunction-associated steatotic liver disease; MASLD; type 2 diabetes; exosomes; glucagon-like peptide 1 receptor agonist; HEPA-REG; LX-2 cells metabolic dysfunction-associated steatotic liver disease; MASLD; type 2 diabetes; exosomes; glucagon-like peptide 1 receptor agonist; HEPA-REG; LX-2 cells

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MDPI and ACS Style

Scavo, M.P.; Lisco, G.; Depalo, N.; Rizzi, F.; Volpe, S.; Arrè, V.; Carrieri, L.; Notarnicola, M.; De Nunzio, V.; Curri, M.L.; et al. Semaglutide Modulates Extracellular Matrix Production of LX-2 Cells via Exosomes and Improves Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). Int. J. Mol. Sci. 2024, 25, 1493. https://doi.org/10.3390/ijms25031493

AMA Style

Scavo MP, Lisco G, Depalo N, Rizzi F, Volpe S, Arrè V, Carrieri L, Notarnicola M, De Nunzio V, Curri ML, et al. Semaglutide Modulates Extracellular Matrix Production of LX-2 Cells via Exosomes and Improves Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). International Journal of Molecular Sciences. 2024; 25(3):1493. https://doi.org/10.3390/ijms25031493

Chicago/Turabian Style

Scavo, Maria Principia, Giuseppe Lisco, Nicoletta Depalo, Federica Rizzi, Sara Volpe, Valentina Arrè, Livianna Carrieri, Maria Notarnicola, Valentina De Nunzio, Maria Lucia Curri, and et al. 2024. "Semaglutide Modulates Extracellular Matrix Production of LX-2 Cells via Exosomes and Improves Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)" International Journal of Molecular Sciences 25, no. 3: 1493. https://doi.org/10.3390/ijms25031493

APA Style

Scavo, M. P., Lisco, G., Depalo, N., Rizzi, F., Volpe, S., Arrè, V., Carrieri, L., Notarnicola, M., De Nunzio, V., Curri, M. L., De Pergola, G., Piazzolla, G., & Giannelli, G. (2024). Semaglutide Modulates Extracellular Matrix Production of LX-2 Cells via Exosomes and Improves Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). International Journal of Molecular Sciences, 25(3), 1493. https://doi.org/10.3390/ijms25031493

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