Biomedicine & Pharmacotherapy (Nov 2023)
Elafibranor upregulates the EMT-inducer S100A4 via PPARβ/δ
- Meijian Zhang,
- Emma Barroso,
- Maria Ruart,
- Lucía Peña,
- Mona Peyman,
- David Aguilar-Recarte,
- Marta Montori-Grau,
- Patricia Rada,
- Clara Cugat,
- Carla Montironi,
- Mohammad Zarei,
- Javier Jurado-Aguilar,
- Antoni Camins,
- Jesús Balsinde,
- Ángela M. Valverde,
- Walter Wahli,
- Xavier Palomer,
- Manuel Vázquez-Carrera
Affiliations
- Meijian Zhang
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences and Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, Spain; Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, Spain; Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain
- Emma Barroso
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences and Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, Spain; Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, Spain; Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain
- Maria Ruart
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences and Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, Spain; Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, Spain; Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain
- Lucía Peña
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences and Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, Spain; Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, Spain; Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain
- Mona Peyman
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences and Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, Spain; Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, Spain; Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain
- David Aguilar-Recarte
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences and Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, Spain; Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, Spain; Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain
- Marta Montori-Grau
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences and Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, Spain; Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, Spain; Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain
- Patricia Rada
- Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, Spain; Instituto de Investigaciones Biomédicas Alberto Sols (CSIC/UAM), Madrid, Spain
- Clara Cugat
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences and Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, Spain; Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, Spain; Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain
- Carla Montironi
- Pathology Department, Hospital Clínic, Barcelona, Spain; Liver Cancer Translational Research Group, Liver Unit, IDIBAPS-Hospital Clínic, University of Barcelona, Spain
- Mohammad Zarei
- John B. Little Center for Radiation Sciences, Harvard T.H. Chan School of Public Health, Boston, USA; Renal Division, Brigham & Women's Hospital, Harvard Medical School, Boston, USA
- Javier Jurado-Aguilar
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences and Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, Spain; Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, Spain; Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain
- Antoni Camins
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences and Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, Spain; Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), Madrid, Spain; Institute of Neuroscience, University of Barcelona, Barcelona, Spain
- Jesús Balsinde
- Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, Spain; Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas, Valladolid, Spain
- Ángela M. Valverde
- Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, Spain; Instituto de Investigaciones Biomédicas Alberto Sols (CSIC/UAM), Madrid, Spain
- Walter Wahli
- Center for Integrative Genomics, University of Lausanne, CH-1015 Lausanne, Switzerland; Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, 308232, Singapore; INRA ToxAlim, UMR1331, Chemin de Tournefeuille, F-31027 Toulouse Cedex 3, France
- Xavier Palomer
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences and Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, Spain; Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, Spain; Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain
- Manuel Vázquez-Carrera
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences and Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, Spain; Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, Spain; Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain; Correspondence to: Unitat de Farmacologia, Facultat de Farmàcia i Ciències de l′Alimentació, Av. Joan XXIII 27-31, E-08028 Barcelona, Spain.
- Journal volume & issue
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Vol. 167
p. 115623
Abstract
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.
