Loss of triggers lipid metabolic disorder through H3K27 acetylation-mediated C/EBPβ- activation in non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is associated with mutations in lipopolysaccharide-binding protein ( ), but the underlying epigenetic mechanisms remain understudied. Herein, rats with NAFLD were established and used to conduct integrative targeting-active enhancer histone H3 lysine 27 acetylation (H3K27ac) chromatin immunoprecipitation coupled with high-throughput and transcriptomic sequencing analysis to explore the potential epigenetic pathomechanisms of active enhancers of NAFLD exacerbation upon deficiency. Notably, reduced the inflammatory response but markedly aggravated high-fat diet (HFD)-induced NAFLD in rats, with pronounced alterations in the histone acetylome and regulatory transcriptome. In total, 1 128 differential enhancer-target genes significantly enriched in cholesterol and fatty acid metabolism were identified between wild-type (WT) and NAFLD rats. Based on integrative analysis, CCAAT/enhancer-binding protein β (C/EBPβ) was identified as a pivotal transcription factor (TF) and contributor to dysregulated histone acetylome H3K27ac, and the lipid metabolism gene was identified as a downstream effector exacerbating NAFLD. This study not only broadens our understanding of the essential role of in the pathogenesis of NAFLD from an epigenetics perspective but also identifies key TF C/EBPβ and functional gene as potential regulators and therapeutic targets.