Abstract:
Non-alcoholic fatty liver disease (NAFLD) is associated with mutations in lipopolysaccharide-binding protein (
LBP), but the underlying epigenetic mechanisms remain understudied. Herein,
LBP-/- 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
LBP deficiency. Notably,
LBP-/- 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
LBP-/- 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
SCD was identified as a downstream effector exacerbating NAFLD. This study not only broadens our understanding of the essential role of
LBP in the pathogenesis of NAFLD from an epigenetics perspective but also identifies key TF C/EBPβ and functional gene
SCD as potential regulators and therapeutic targets.
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