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

• Published in: Dōngwùxué yánjiū 2024-01, Vol.45 (1), p.79-94
• Main Authors: Zhu, Ya-Ling, Meng, Lei-Lei, Ma, Jin-Hu, Yuan, Xin, Chen, Shu-Wen, Yi, Xin-Rui, Li, Xin-Yu, Wang, Yi, Tang, Yun-Shu, Xue, Min, Zhu, Mei-Zi, Peng, Jin, Lu, Xue-Jin, Huang, Jian-Zhen, Song, Zi-Chen, Wu, Chong, Zheng, Ke-Zhong, Dai, Qing-Qing, Huang, Fan, Fang, Hao-Shu
• Format: Article
• Language: English
• Subjects: Acetylation; Animals; Carbohydrates; CCAAT/enhancer-binding protein; Cholesterol; Chromatin; Enhancers; Epigenetics; Fatty acids; Fatty liver; Genes; Genomes; High fat diet; Histone H3; Histones; Immunoprecipitation; Inflammation; Inflammatory response; Lipid metabolism; Lipids; Lipopolysaccharide-binding protein; Lipopolysaccharides; Liver; Liver diseases; Localization; Lysine; Metabolic disorders; Mutation; Pathogenesis; Proteins; Sequence analysis; Therapeutic targets; Transcription; Transcription factors; Transcriptomes; Transcriptomics
• ISSN: 0254-5853
• DOI: 10.24272/j.issn.2095-8137.2023.022

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 pathomechan isms 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 ß (C/EBPß) 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/EBPß and functional gene SCD as potential regulators and therapeutic targets.