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. 2024 Jan 18;45(1):79-94.
doi: 10.24272/j.issn.2095-8137.2023.022.

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

Ya-Ling Zhu  1   2 , Lei-Lei Meng  1 , Jin-Hu Ma  1 , Xin Yuan  1 , Shu-Wen Chen  1 , Xin-Rui Yi  1 , Xin-Yu Li  1 , Yi Wang  1 , Yun-Shu Tang  1   2 , Min Xue  1 , Mei-Zi Zhu  1 , Jin Peng  1 , Xue-Jin Lu  1 , Jian-Zhen Huang  3 , Zi-Chen Song  1 , Chong Wu  1 , Ke-Zhong Zheng  4 , Qing-Qing Dai  4 , Fan Huang  5 , Hao-Shu Fang  1   6
Affiliations

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

Ya-Ling Zhu et al. Zool Res. .

Abstract
in English, Chinese

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.

非酒精性脂肪肝（NAFLD）已被广泛报道与脂多糖结合蛋白（ LBP）存在潜在联系。然而，支撑这种潜在联系的机制，特别是表观调控机制仍不清楚。在该研究中，我们构建了患有NAFLD的 LBP基因敲除大鼠模型，并通过整合分析肝脏H3K27ac ChIP-Seq和RNA-Seq数据探索活性增强子标志物H3K27ac在 LBP基因缺失加重NAFLD病情过程中的潜在表观调控机制。有趣的是，我们发现 LBP基因缺失虽可减轻肝脏炎症反应，但会明显加重大鼠NAFLD病情进展，并导致肝脏组蛋白乙酰组和转录组特征发生明显改变。在野生型和 LBP基因敲除NAFLD大鼠之间共发现1128个显著富集于“胆固醇代谢过程”和“脂肪酸代谢过程”的差异峰-基因。值得注意的是，基于对H3K27ac ChIP-Seq和RNA-Seq数据的整合分析，我们分别筛选出转录因子C/EBPβ和脂质代谢基因 SCD作为上游H3K27ac活性改变以及下游肝细胞脂质沉积加重的关键因素。综上，该研究不仅从表观遗传学的角度拓宽了我们对 LBP在NAFLD发病机制中的重要作用的认识，而且确定转录因子 C/EBPβ和枢纽基因 SCD作为参与NAFLD病情进展的关键因子，具有潜在的临床推广价值。.

Keywords: C/EBPβ; Enhancer; H3K27ac; Integrative analysis; Lipopolysaccharide-binding protein; Non-alcoholic fatty liver disease.

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Conflict of interest statement

The authors declare they have no competing interests.

Figures

Figure 1
Figure 1
LBP knockout reduces inflammatory response but exacerbates HFD-induced NAFLD process in rats
Figure 2
Figure 2
Hepatocyte-specific knockdown of LBP diminishes lipid accumulation
Figure 3
Figure 3
Integrative analysis of acetylome and transcriptome reveals upstream transcription factor C/EBPβ
Figure 4
Figure 4
Regulatory process of C/EBPβ on LBP is highly consistent across humans, rats, and mice
Figure 5
Figure 5
LBP deficiency regulates expression of downstream lipid metabolism gene SCD through H3K27ac
Figure 6
Figure 6
C/EBPβ facilitates expression of downstream lipid metabolism gene SCD
Figure 7
Figure 7
Regulatory mechanism of SCD aggravating lipid metabolic disorder of HFD-induced NAFLD with LBP deficiency
Figure 8
Figure 8
Proposed model of LBP deficiency exacerbating HFD-induced NAFLD pathogenesis
See this image and copyright information in PMC

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