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000646269 1001_ $$aPapa, Christina$$b0
000646269 245__ $$aBempedoic acid directly binds and activates PPARα
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000646269 520__ $$aBempedoic 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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000646269 7001_ $$aRose, Alina$$b1
000646269 7001_ $$aMartin, Hugo N. G.$$b2
000646269 7001_ $$aUseini, Abibe$$b3
000646269 7001_ $$aGeier, Florian$$b4
000646269 7001_ $$aLiao, Longsheng$$b5
000646269 7001_ $$aRodríguez-Aguilera, Jesús Rafael$$b6
000646269 7001_ $$aValina-Allo, Philipp$$b7
000646269 7001_ $$aHoffmann, Anne$$b8
000646269 7001_ $$aTvardovskiy, Andrey$$b9
000646269 7001_ $$aZulfqar, Faiqa$$b10
000646269 7001_ $$aZimmerman, Andrea$$b11
000646269 7001_ $$aSchicht, Gerda$$b12
000646269 7001_ $$aOtt, Fritzi$$b13
000646269 7001_ $$aKörner, Christiane$$b14
000646269 7001_ $$aEngelmann, Beatrice$$b15
000646269 7001_ $$aRolle-Kampczyk, Ulrike$$b16
000646269 7001_ $$avon Bergen, Martin$$b17
000646269 7001_ $$aMeier, Matthias$$b18
000646269 7001_ $$aBartke, Till$$b19
000646269 7001_ $$aSeehofer, Daniel$$b20
000646269 7001_ $$aKlöting, Nora$$b21
000646269 7001_ $$aMatz-Soja, Madlen$$b22
000646269 7001_ $$aDamm, Georg$$b23
000646269 7001_ $$aBoeckel, Jes-Niels$$b24
000646269 7001_ $$aBuescher, Joerg M.$$b25
000646269 7001_ $$aBlüher, Matthias$$b26
000646269 7001_ $$aLaufs, Ulrich$$b27
000646269 7001_ $$aBondareva, Olga$$b28
000646269 7001_ $$aSträter, Norbert$$b29
000646269 7001_ $$aKünze, Georg$$b30
000646269 7001_ $$aHeiker, John T.$$b31
000646269 7001_ $$00000-0002-1970-6236$$aSheikh, Bilal N.$$b32$$eCorresponding author
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000646269 8564_ $$uhttps://www.cell.com/cell-metabolism/fulltext/S1550-4131(25)00549-2
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