Hui-Mei Liang, Yin-Yue Xu, Kun Miao, Hai-Tao Xiao, Yong-Dan Wang, Jing Jin, He Wu, Bao-Yi Chen, Li-Jun Xu, Jiang-Ping Zhu, Li-Na Lai, Zu-Guo Zheng
AS-IV uniquely downregulates GCN5 expression at the transcriptional level, exerting epigenetic regulation to disrupts lipogenic programming, This represents a novel multi-target approach against MASLD that connects natural product pharmacology with epigenetic modulation.
BACKGROUND: Astragaloside IV (AS-IV), a bioactive saponin from Astragalus membranaceus, shows promise for treating metabolic dysfunction-associated steatotic liver disease (MASLD), though its mechanisms remain unclear.
PURPOSE: This study aimed to elucidate how AS-IV alleviates hepatic steatosis, specifically investigating its epigenetic regulation of lipogenesis.
METHODS: Using high-fat diet-fed mice and lipids-loaded hepatocytes, we assessed AS-IV's effects through SREBP-1c overexpression, histone acetylation analysis, and GCN5 rescue experiments.
RESULTS: AS-IV significantly reduced hepatic steatosis by suppressing SREBP-1c-mediated de novo lipogenesis. Mechanistically, it inhibited histone acetyltransferase GCN5, decreasing H3K9/H3K14 acetylation at the SREBP-1c promoter and attenuating LXRα-driven transcription. GCN5 overexpression reversed AS-IV's suppression of SREBP-1c and lipid accumulation.
CONCLUSION: AS-IV uniquely downregulates GCN5 expression at the transcriptional level, exerting epigenetic regulation to disrupts lipogenic programming, This represents a novel multi-target approach against MASLD that connects natural product pharmacology with epigenetic modulation.