Elafibranor upregulates the EMT-inducer S100A4 via PPARβ/δ
Elafibranor is a dual peroxisome proliferator-activated receptor (PPAR)α and β/δ agonist that has reached a phase III clinical trial for the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we examined the effects of elafibranor in mice fed a choline-deficient hig...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
| Published: |
2024
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| Subjects: | |
| Online Access: | https://hdl.handle.net/10356/174274 |
| _version_ | 1811677833279307776 |
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| author | Zhang, Meijian Barroso, Emma Ruart, Maria Peña, Lucía Peyman, Mona Aguilar-Recarte, David Montori-Grau, Marta Rada, Patricia Cugat, Clara Montironi, Carla Zarei, Mohammad Jurado-Aguilar, Javier Camins, Antoni Balsinde, Jesús Valverde, Ángela M. Wahli, Walter Palomer, Xavier Vázquez-Carrera, Manuel |
| author2 | Lee Kong Chian School of Medicine (LKCMedicine) |
| author_facet | Lee Kong Chian School of Medicine (LKCMedicine) Zhang, Meijian Barroso, Emma Ruart, Maria Peña, Lucía Peyman, Mona Aguilar-Recarte, David Montori-Grau, Marta Rada, Patricia Cugat, Clara Montironi, Carla Zarei, Mohammad Jurado-Aguilar, Javier Camins, Antoni Balsinde, Jesús Valverde, Ángela M. Wahli, Walter Palomer, Xavier Vázquez-Carrera, Manuel |
| author_sort | Zhang, Meijian |
| collection | NTU |
| description | Elafibranor is a dual peroxisome proliferator-activated receptor (PPAR)α and β/δ agonist that has reached a phase III clinical trial for the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we examined the effects of elafibranor in mice fed a choline-deficient high-fat diet (CD-HFD), a model of metabolic dysfunction-associated steatohepatitis (MASH) that presents obesity and insulin resistance. Our findings revealed that elafibranor treatment ameliorated steatosis, inflammation, and fibrogenesis in the livers of CD-HFD-fed mice. Unexpectedly, elafibranor also increased the levels of the epithelial-mesenchymal transition (EMT)-promoting protein S100A4 via PPARβ/δ activation. The increase in S100A4 protein levels caused by elafibranor was accompanied by changes in the levels of markers associated with the EMT program. The S100A4 induction caused by elafibranor was confirmed in the BRL-3A rat liver cells and a mouse primary hepatocyte culture. Furthermore, elafibranor reduced the levels of ASB2, a protein that promotes S100A4 degradation, while ASB2 overexpression prevented the stimulating effect of elafibranor on S100A4. Collectively, these findings reveal an unexpected hepatic effect of elafibranor on increasing S100A4 and promoting the EMT program. |
| first_indexed | 2024-10-01T02:43:39Z |
| format | Journal Article |
| id | ntu-10356/174274 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T02:43:39Z |
| publishDate | 2024 |
| record_format | dspace |
| spelling | ntu-10356/1742742024-03-31T15:39:59Z Elafibranor upregulates the EMT-inducer S100A4 via PPARβ/δ Zhang, Meijian Barroso, Emma Ruart, Maria Peña, Lucía Peyman, Mona Aguilar-Recarte, David Montori-Grau, Marta Rada, Patricia Cugat, Clara Montironi, Carla Zarei, Mohammad Jurado-Aguilar, Javier Camins, Antoni Balsinde, Jesús Valverde, Ángela M. Wahli, Walter Palomer, Xavier Vázquez-Carrera, Manuel Lee Kong Chian School of Medicine (LKCMedicine) Medicine, Health and Life Sciences Metabolic dysfunction-associated steatotic liver disease Epithelial-mesenchymal transition Elafibranor is a dual peroxisome proliferator-activated receptor (PPAR)α and β/δ agonist that has reached a phase III clinical trial for the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we examined the effects of elafibranor in mice fed a choline-deficient high-fat diet (CD-HFD), a model of metabolic dysfunction-associated steatohepatitis (MASH) that presents obesity and insulin resistance. Our findings revealed that elafibranor treatment ameliorated steatosis, inflammation, and fibrogenesis in the livers of CD-HFD-fed mice. Unexpectedly, elafibranor also increased the levels of the epithelial-mesenchymal transition (EMT)-promoting protein S100A4 via PPARβ/δ activation. The increase in S100A4 protein levels caused by elafibranor was accompanied by changes in the levels of markers associated with the EMT program. The S100A4 induction caused by elafibranor was confirmed in the BRL-3A rat liver cells and a mouse primary hepatocyte culture. Furthermore, elafibranor reduced the levels of ASB2, a protein that promotes S100A4 degradation, while ASB2 overexpression prevented the stimulating effect of elafibranor on S100A4. Collectively, these findings reveal an unexpected hepatic effect of elafibranor on increasing S100A4 and promoting the EMT program. Published version This study was partly supported by the grants RTI2018-093999-B- I00 and PID2021-122116OB-I00 (M.V-C.), PID2021-122766OB-I00 (A. M.V.), and PID2019-105989RB-I00 (J.B.) from MCIN/AEI/10.13039/ 501100011033 and “ERDF, A Way of Making Europe”. CIBER de Diabetes y Enfermedades Metab´ olicas Asociadas (CIBERDEM) is a Carlos III Health Institute project. Support was also received from the CERCA Programme/Generalitat de Catalunya. Meijian Zhang was supported by a grant from the China Scholarship Council (CSC) (202007565030). 2024-03-25T05:13:45Z 2024-03-25T05:13:45Z 2023 Journal Article Zhang, M., Barroso, E., Ruart, M., Peña, L., Peyman, M., Aguilar-Recarte, D., Montori-Grau, M., Rada, P., Cugat, C., Montironi, C., Zarei, M., Jurado-Aguilar, J., Camins, A., Balsinde, J., Valverde, Á. M., Wahli, W., Palomer, X. & Vázquez-Carrera, M. (2023). Elafibranor upregulates the EMT-inducer S100A4 via PPARβ/δ. Biomedicine and Pharmacotherapy, 167, 115623-. https://dx.doi.org/10.1016/j.biopha.2023.115623 0753-3322 https://hdl.handle.net/10356/174274 10.1016/j.biopha.2023.115623 37783154 2-s2.0-85172870845 167 115623 en Biomedicine and Pharmacotherapy © 2023 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). application/pdf |
| spellingShingle | Medicine, Health and Life Sciences Metabolic dysfunction-associated steatotic liver disease Epithelial-mesenchymal transition Zhang, Meijian Barroso, Emma Ruart, Maria Peña, Lucía Peyman, Mona Aguilar-Recarte, David Montori-Grau, Marta Rada, Patricia Cugat, Clara Montironi, Carla Zarei, Mohammad Jurado-Aguilar, Javier Camins, Antoni Balsinde, Jesús Valverde, Ángela M. Wahli, Walter Palomer, Xavier Vázquez-Carrera, Manuel Elafibranor upregulates the EMT-inducer S100A4 via PPARβ/δ |
| title | Elafibranor upregulates the EMT-inducer S100A4 via PPARβ/δ |
| title_full | Elafibranor upregulates the EMT-inducer S100A4 via PPARβ/δ |
| title_fullStr | Elafibranor upregulates the EMT-inducer S100A4 via PPARβ/δ |
| title_full_unstemmed | Elafibranor upregulates the EMT-inducer S100A4 via PPARβ/δ |
| title_short | Elafibranor upregulates the EMT-inducer S100A4 via PPARβ/δ |
| title_sort | elafibranor upregulates the emt inducer s100a4 via pparβ δ |
| topic | Medicine, Health and Life Sciences Metabolic dysfunction-associated steatotic liver disease Epithelial-mesenchymal transition |
| url | https://hdl.handle.net/10356/174274 |
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