德国亥姆霍兹代谢研究所Bilal N. Sheikh团队探明了苯二甲酸直接结合并激活PPARα。该研究于2026年1月26日发表于国际一流学术期刊《细胞—代谢》杂志上。

该课题组研究人员结合转录组学、生化和结构方法，证明BA直接结合并激活过氧化物酶体增殖物激活受体α (PPARα)。BA处理可诱导原代肝细胞和母代肝细胞PPARα信号通路和脂肪酸氧化。通过x射线晶体学，该课题组发现BA与PPARα的配体结合域结合并稳定其活性构象。BA独立于超长链酰基辅酶A （CoA）合成酶（ACSVL1）激活PPARα靶基因，ACSVL1是肝脏富集酶，可将BA转化为苯甲酰基辅酶A形式。值得注意的是，BA介导的脂肪酸氧化诱导需要PPARα。总之，这项工作揭示了直接激活PPARα作为BA作用的关键机制，为其降脂作用提供了分子基础，并表明其在肝脏以外的更广泛的治疗潜力。

研究人员表示，苯二甲酸（BA）是最近被批准的一种降低胆固醇和肝脂质的药物，但其作用机制仍不完全清楚。

附：英文原文

Title: Bempedoic acid directly binds and activates PPARα

Author: Christina Papa, Alina Rose, Hugo N.G. Martin, Abibe Useini, Florian Geier, Longsheng Liao, Jesús Rafael Rodríguez-Aguilera, Philipp Valina-Allo, Anne Hoffmann, Andrey Tvardovskiy, Faiqa Zulfqar, Andrea Zimmerman, Gerda Schicht, Fritzi Ott, Christiane Krner, Beatrice Engelmann, Ulrike Rolle-Kampczyk, Martin von Bergen, Matthias Meier, Till Bartke, Daniel Seehofer, Nora Klting, Madlen Matz-Soja, Georg Damm, Jes-Niels Boeckel, Joerg M. Buescher, Matthias Blüher, Ulrich Laufs, Olga Bondareva, Norbert Strter, Georg Künze, John T. Heiker, Bilal N. Sheikh

Issue&Volume: 2026-01-26

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.

DOI: 10.1016/j.cmet.2025.12.018

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(25)00549-2