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

Non-alcoholic fatty liver disease (NAFLD) has been widely reported to have a potential association with LBP (Lipopolysaccharide-binding protein) mutation. However, the mechanisms, especially epigenetic mechanisms underpinning the association remain elusive. Herein, we constructed LBP-/- rats with NAFLD and performed integrative analysis of targeting-active enhancer H3K27ac chromatin immunoprecipitation coupled with high-throughput sequencing and transcriptomic sequencing to explore the potential epigenetic pathomechanisms of active enhancer in the exacerbation of NAFLD upon LBP deficiency. Intriguingly, we found that LBP-/- could reduce inflammatory response but markedly deteriorate HFD-induced NAFLD in rats, with abundant alterations of histone acetylome and regulatory transcriptome. In total, 1,128 differential enhancer-target genes significantly enriched in cholesterol metabolic process and fatty acid metabolic process were identified with | Cor (peak-gene correlation) | > 0.5 and a | log2 (fold change) | > 1.5 between WT and LBP-/- NAFLD rats. Notably, based on our integrative analysis method, we screened out TF C/EBPβ (CCAAT/enhancer-binding protein β) as a pivotal contributor to dysregulated histone acetylome H3K27ac and lipid metabolism gene SCD as a downstream effector to exacerbate NAFLD. Thus, this study not only broadens our understanding of the essential role of LBP in the pathogenesis of NAFLD from the perspective of epigenetics, but identifies key TF C/EBPβ and hub functional gene SCD as potential regulators that may serve as possible therapeutic targets.