Short-chain fatty acids in nonalcoholic fatty liver disease: New prospects for short-chain fatty acids as therapeutic targets.

Nonalcoholic fatty liver disease (NAFLD) is a stress-induced liver injury related to heredity, environmental exposure and the gut microbiome metabolism. Short-chain fatty acids (SCFAs), the metabolites of gut microbiota (GM), participate in the regulation of hepatic steatosis and inflammation through the gut-liver axis, which play an important role in the alleviation of NAFLD. However, little progress has been made in systematically elucidating the mechanism of how SCFAs improve NAFLD, especially the epigenetic mechanisms and the potential therapeutic application as clinical treatment for NAFLD. Herein, we adopted PubMed and Medline to search relevant keywords such as 'SCFAs', 'NAFLD', 'gut microbiota', 'Epigenetic', 'diet', and 'prebiotic effect' to review the latest research on SCFAs in NAFLD up to November 2023. In this review, firstly, we specifically discussed the production and function of SCFAs, as well as their crosstalk coordination in the gut liver axis. Secondly, we provided an updated summary and intensive discussion of how SCFAs affect hepatic steatosis to alleviate NAFLD from the perspective of genetic and epigenetic. Thirdly, we paid attention to the pharmacological and physiological characteristics of SCFAs, and proposed a promising future direction to adopt SCFAs alone or in combination with prebiotics and related clinical drugs to prevent and treat NAFLD. Together, this review aimed to elucidate the function of SCFAs and provide new insights to the prospects of SCFAs as a therapeutic target for NAFLD.

Epigenetic regulation of key gene of PCK1 by enhancer and super-enhancer in the pathogenesis of fatty liver hemorrhagic syndrome.

OBJECTIVE: Rare study of the non-coding and regulatory regions of the genome limits our ability to decode the mechanisms of fatty liver hemorrhage syndrome (FLHS) in chickens. METHODS: Herein, we constructed the high-fat diet-induced FLHS chicken model to investigate the genome-wide active enhancers and transcriptome by H3K27ac target chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-Seq) profiles of normal and FLHS liver tissues. Concurrently, an integrative analysis combining ChIP-seq with RNA-Seq and a comparative analysis with chicken FLHS, rat non-alcoholic fatty liver disease (NAFLD) and human NAFLD at the transcriptome level revealed the enhancer and super enhancer target genes and conservative genes involved in metabolic processes. RESULTS: In total, 56 and 199 peak-genes were identified in upregulated peak-genes positively regulated by H3K27ac (Cor (peak-gene correlation) ≥0.5 and log2(FoldChange) ≥1) (PP) and downregulated peak-genes positively regulated by H3K27ac (Cor (peak-gene correlation) ≥0.5 and log2(FoldChange)≤-1) (PN), respectively; then we screened key regulatory targets mainly distributing in lipid metabolism (PCK1, APOA4, APOA1, INHBE) and apoptosis (KIT, NTRK2) together with MAPK and PPAR signaling pathway in FLHS. Intriguingly, PCK1 was also significantly covered in up-regulated super-enhancers (SEs), which further implied the vital role of PCK1 during the development of FLHS. CONCLUSION: Together, our studies have identified potential therapeutic biomarkers of PCK1 and elucidated novel insights into the pathogenesis of FLHS, especially for the epigenetic perspective.

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

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 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.

Epigenetic association study uncovered H3K27 acetylation enhancers and dysregulated genes in high-fat-diet-induced nonalcoholic fatty liver disease in rats.

Aim: To evaluate the regulatory landscape underlying the active enhancer marked by H3K27ac in high-fat diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD) in rats. Materials & methods: H3K27ac chromatin immunoprecipitation and high-throughput RNA sequencing to construct regulatory profiles and transcriptome of liver from NAFLD rat model induced by HFD. De novo motif analysis for differential H3K27ac peaks. Functional enrichment, Kyoto Encyclopedia of Genes and Genomes pathway and protein-protein interaction network were examined for differential peak-genes. The mechanism was further verified by western blot, chromatin immunoprecipitation-quantitative PCR and real-time PCR. Results: A total of 1831 differential H3K27ac peaks were identified significantly correlating with transcription factors and target genes (CYP8B1, PLA2G12B, SLC27A5, CYP7A1 and APOC3) involved in lipid and energy homeostasis. Conclusion: Altered acetylation induced by HFD leads to the dysregulation of gene expression, further elucidating the epigenetic mechanism in the etiology of NAFLD.

What is this summary about? Nonalcoholic fatty liver disease (NAFLD) is a typical metabolic disease, which is becoming the most common liver disease in the world. Despite its high prevalence and morbidity, there is currently no effective diagnostic or approved therapy, and the molecular mechanisms for NAFLD have not been fully clarified, especially for epigenetics. Herein, we focused on histone modification and investigated the impact of active enhancer to explore the epigenetic regulation of NAFLD, seeking new targets for the prevention and treatment of the disease. What were the results? We identified the alteration of H3K27 acetylation and differential gene expression, enriched potential transcription-factor binding motifs and highlighted the hub risk genes of CYP8B1, PLA2G12B, SLC27A5, CYP7A1 and APOC3 in a NAFLD rat model. What do the results mean? This work emphasized the vital roles of histone modification of H3K27ac in a high-fat-diet-induced NAFLD model, which could regulate the expression of key genes and transcription factor binding motifs, and H3K27ac induced the formation of NAFLD. Targeting the H3K27ac modification, dysregulated target genes and enriched pathways may be of great importance for NAFLD prediction and prevention, and serve as a valuable resource for genome-wide studies of epigenomic regulation in lipid metabolic disease.