GCN5 drives NAFLD progression through LXRα/SREBP1c signaling pathway-mediated de novo lipogenesis

Non-alcoholic fatty liver disease (NAFLD) is a prevalent health concern globally, impacting around a quarter of the world's population. General control non-repressed protein 5 (GCN5) is histone acetyltransferases (HATs) and is closely related to the progression of multiple diseases, but the role of GCN5 in NAFLD has not been reported. In this study, our data demonstrated that performed in progressive human and murine NAFLD provided the first experimental evidence for the role of GCN5, but not p300/CREB binding protein associated factor (PCAF) activation in disease acceleration. Hepatocyte-specific overexpression of GCN5 exacerbated the progression of NAFLD, while hepatic GCN5 ablation suppressed it. CPTH2, a potent GCN5 inhibitor, protects against NAFLD. Targeted lipidomics analysis identified a pivotal role of GCN5 simultaneously promoting de novo lipogenesis (DNL) by increasing SREBP1c-mediated expression of target genes. GCN5 promotes gene expression of SREBP1c by altering the acetylation state of histone 3 in the promoter region of SREBP1c through its inherent acetyltransferase activity. Our study demonstrates that GCN5 is involved in the transcriptional regulation of LXRα-stimulated SREBP1c. Modulating GCN5 could serve as a strategy to selectively inhibit SREBP1c-mediated lipid biosynthesis while maintaining LXRα-stimulated reverse cholesterol transport (RCT). Moreover, combined administration of LXR agonist T0901317 and CPTH2 may play a synergistic lipid-lowering effect in vitro and in vivo.