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Papa, C. ; Rose, A. ; Martin, H.N.G. ; Useini, A.* ; Geier, F. ; Liao, L. ; Rodriguez Aguilera, J.R. ; Valina-Allo, P. ; Hoffmann, A. ; Tvardovskiy, A. ; Zulfqar, F. ; Zimmerman, A.* ; Schicht, G.* ; Ott, F.* ; Körner, C.* ; Engelmann, B.* ; Rolle-Kampczyk, U.* ; von Bergen, M.* ; Meier, M. ; Bartke, T. ; Seehofer, D.* ; Klöting-Blüher, N. ; Matz-Soja, M.* ; Damm, G.* ; Boeckel, J.N.* ; Buescher, J.M.* ; Blüher, M. ; Laufs, U.* ; Bondareva, O. ; Sträter, N.* ; Künze, G.* ; Heiker, J.T. ; Sheikh, B.N.

Bempedoic acid directly binds and activates PPARα.

Cell Metab., DOI: 10.1016/j.cmet.2025.12.018 (2026)
Verlagsversion Forschungsdaten DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
Bempedoic acid (BA) is a recently approved drug that lowers cholesterol and hepatic lipids, yet its mechanism of action remains incompletely understood. Here, we combine transcriptomic, biochemical, and structural approaches to show that BA directly binds to and activates peroxisome proliferator-activated receptor alpha (PPARα). BA treatment robustly induced PPARα signaling and fatty acid oxidation in primary hepatocytes and mouse liver. Through X-ray crystallography, we uncovered that BA binds to the ligand-binding domain of PPARα and stabilizes its active conformation. BA activated PPARα target genes independently of very-long-chain acyl-coenzyme A (CoA) synthetase (ACSVL1), the liver-enriched enzyme that converts BA to its bempedoyl-CoA form. Notably, BA-mediated induction of fatty acid oxidation required PPARα. Together, this work reveals direct PPARα activation as a key mechanism of BA action, providing a molecular basis for its lipid-lowering effects and suggesting broader therapeutic potential beyond the liver.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Ppar ; Cardiovascular ; Cholesterol ; Lipids ; Metabolism ; Transcription
ISSN (print) / ISBN 1550-4131
e-ISSN 1932-7420
Zeitschrift Cell Metabolism
Verlag Elsevier
Begutachtungsstatus Peer reviewed
Institut(e) Helmholtz Institute for Metabolism, Obesity and Vascular Research (HI-MAG)
Institute of Functional Epigenetics (IFE)
Helmholtz Pioneer Campus (HPC)