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

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.

Overexpression of wild-type HRAS drives non-alcoholic steatohepatitis to hepatocellular carcinoma in mice

“…Additionally, 1 573 DEGs were shared across both time points ( Figure 6B ; Supplementary Table S6). Based on KEGG analysis, these DEGs were primarily enriched in lipid metabolism pathways, such as arachidonic acid metabolism, retinol metabolism, and steroid hormone biosynthesis ( Figure 6C ; Supplementary Table S7), all of which are associated with NAFLD ( Zhu et al, 2024 ). Further analysis revealed the regulatory relationships between HRAS and the top 100 up-regulated and down-regulated DEGs through PPI network (Supplementary Figure S5A) and Cytoscape analyses.…”

The relevance of intestinal barrier dysfunction, antimicrobial proteins and bacterial endotoxin in metabolic dysfunction‐associated steatotic liver disease

“…Although previous experimental studies in mice and rats supported this idea, 83–86 experiments in hepatocytes demonstrated a proinflammatory effect of LBP gene knockdown in the absence of LPS, which could be produced by other causes, such as oxidative stress and perturbations in cellular lipidomic signature 82,87 . Furthermore, two recent studies go against the detrimental effect of LBP on MASLD progression in obesity, 88,89 suggesting that further mechanistic studies are required to clarify the impact of LBP on liver physiology and metabolism, and molecular processes underlying these effects.…”