Gualou total alkaloids improve lipid metabolism and alleviate atherosclerosis by inhibiting hepatic PLA2G2A-mediated...

Atherosclerosis (AS), marked by lipid-induced arterial plaques, is closely related to liver lipid metabolism dysfunction. Gualou Total Alkaloids (GLTA), derived from Gualou, a traditional Chinese medicine (TCM) renowned for its lipid-lowering effects. However, the potential of GLTA to address the pathophysiology of AS remains unclear.

This study investigates the therapeutic effects of GLTA on AS, focusing on its impact on hepatic lipid metabolism and key signaling pathways.

GLTA was extracted via acid-base precipitation, and its components analyzed by UPLC-Q-TOF-MS. Its effects were assessed in a high-fat diet-induced ApoE^-/- mouse model of AS, measuring aortic lipid deposition, plaque formation, blood lipids, and hepatic lipid accumulation. Transcriptomic and metabolomic analyses identified key molecular targets. In vivo and in vitro assays confirmed GLTA's mechanism of targeting Phospholipase A2 group II A (PLA2G2A) in hepatic lipid accumulation. Molecular docking, dynamics simulation, Cellular Thermal Shift Assay (CETSA), and functional assays identified key active components in GLTA that inhibit liver lipid accumulation via PLA2G2A.

GLTA reduced plaque formation, improved dyslipidemia, and alleviated hepatic lipid accumulation and steatosis in AS mice. Gene expression analysis identified PLA2G2A as a key target. In vivo, GLTA reversed PLA2G2A-induced hepatic lipid metabolism disruption and inhibited AS progression. Analysis of lipid metabolites showed elevated Lysophosphatidylcholine (LPC) levels in the AS model, which were significantly reduced by GLTA, correlating with its inhibition of PLA2G2A. In vitro, GLTA suppressed the LPC/lysophosphatidic acid (LPA) axis via PLA2G2A inhibition. Trigonelline, identified as a core active component, directly targets PLA2G2A, confirming GLTA's anti-atherosclerotic mechanism.

This study reveals for the first time that GLTA combats AS by targeting PLA2G2A to disrupt the hepatic LPC/LPA axis. This finding highlights both GLTA's potential as a novel anti-AS drug candidate and establishes PLA2G2A as an important therapeutic target for regulating liver function and lipid metabolism during the process of AS.