Biomed Pharmacother. co-auth.: W.Wahli

Elafibranor upregulates the EMT-inducer S100A4 via PPARβ/δ

Meijian Zhang 1Emma Barroso 1Maria Ruart 1Lucía Peña 1Mona Peyman 1David Aguilar-Recarte 1Marta Montori-Grau 1Patricia Rada 2Clara Cugat 1Carla Montironi 3Mohammad Zarei 4Javier Jurado-Aguilar 1Antoni Camins 5Jesús Balsinde 6Ángela M Valverde 2Walter Wahli 7Xavier Palomer 1Manuel Vázquez-Carrera 8

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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.