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...

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Detalles Bibliográficos
Autores: 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
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2023
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/342383
Acceso en línea:http://hdl.handle.net/10261/342383
Access Level:acceso abierto
Palabra clave:MASLD
Elafibranor
PPARβ/δ
S100A4
ASB2
EMT
Descripción
Sumario: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.

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