Journal Article

PUBDB-2026-00792

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Bempedoic acid directly binds and activates PPARα

Papa, C. ; Rose, A. ; Martin, H. N. G. ; Useini, A. ; Geier, F. ; Liao, L. ; Rodríguez-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, 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. (Corresponding author)

2026
Elsevier Amsterdam [u.a.]

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Please use a persistent id in citations: doi:10.1016/j.cmet.2025.12.018

Abstract: 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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Contributing Institute(s):

1. EMBL-User (EMBL-User)

Research Program(s):

1. 6G3 - PETRA III (DESY) (POF4-6G3) (POF4-6G3)

Experiment(s):

1. PETRA Beamline P14 (PETRA III)

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Essential Science Indicators ; IF >= 25 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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