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

Author:

Scavo Maria Principia1ORCID,Lisco Giuseppe2ORCID,Depalo Nicoletta3ORCID,Rizzi Federica3ORCID,Volpe Sara2,Arrè Valentina1,Carrieri Livianna1ORCID,Notarnicola Maria4ORCID,De Nunzio Valentina4ORCID,Curri Maria Lucia5,De Pergola Giovanni6ORCID,Piazzolla Giuseppina2ORCID,Giannelli Gianluigi7ORCID

Affiliation:

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

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.

Funder

Ministero della Salute

Publisher

MDPI AG

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