Sodium butyrate alleviates deoxynivalenol-induced hepatic cholesterol metabolic dysfunction via RORγ-mediated histone acetylation modification in weaning piglets

Abstract

Background Cholesterol is an essential component of lipid rafts in cell plasma membrane, which exerts a hepatoprotective role against mycotoxin exposure in pigs, and cholesterol metabolism is vulnerable to epigenetic histone acetylation. Therefore, our present study aimed to investigate whether a histone deacetylase inhibitor (sodium butyrate [NaBu]) could protect the porcine liver from deoxynivalenol (DON) exposure by modulating cholesterol metabolism. Herein, we randomly divided 28 pigs into four groups, which were fed an uncontaminated basal diet, contaminated diet (4 mg DON/kg), uncontaminated diet supplemented with 0.2% NaBu or 4 mg/kg DON contaminated diet (4 mg DON/kg) supplemented with 0.2% NaBu for 28 d. Results We found that the serum alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP) were all increased in pigs exposed to DON, indicative of significant liver injury. Furthermore, the cholesterol content in the serum of DON-exposed pigs was significantly reduced, compared to the healthy Vehicle group. Transcriptome analysis of porcine liver tissues revealed that the cholesterol homeostasis pathway was highly enriched due to DON exposure. In which we validated by qRT-PCR and western blotting that the cholesterol program was markedly activated. Importantly, NaBu effectively restored parameters associated with liver injury, along with the cholesterol content and the expression of key genes involved in the cholesterol biosynthesis pathway. Mechanistically, we performed a ChIP-seq analysis of H3K27ac and showed that NaBu strongly diminished DON-increased H3K27ac genome-wide enrichment. We further validated that the elevated H3K27ac and H3K9ac occupancies on cholesterol biosynthesis genes were both decreased by NaBu, as determined by ChIP-qPCR analysis. Notably, nuclear receptor RORγ, a novel regulator of cholesterol biosynthesis, was found in the hyperacetylated regions. Again, a remarkable increase of RORγ at both mRNA and protein levels in DON-exposed porcine livers was drastically reduced by NaBu. Consistent with RORγ expression, NaBu also hindered RORγ transcriptional binding enrichments on these activated cholesterol biosynthesis genes like HMGCR, SQLE, and DHCR24. Furthermore, we conducted an in vitro luciferase reporter assay to verify that porcine RORγ directly bonds to the promoters of the above target genes. Conclusions Collectively, our results demonstrate the utility of the natural product NaBu as a potential anti-mycotoxin nutritional strategy for regulating cholesterol metabolism via RORγ-mediated histone acetylation modification.

Effects of dietary sodium butyrate on growth performance, immune function, and intestinal microflora of Chinese soft-shelled turtle (Pelodiscus sinensis)

“…Biochemical indexes are important parameters for assessing the welfare of aquatic animals ( Mitranescu et al., 2013 ), and adjusting these indexes can better meet the living conditions of aquatic animals and promote their growth and development. In our study, TC levels in the blood of Chinese soft-shelled turtles fed with SB were lower than those of turtles fed without it, and this was closely related to the increase in SB concentration ( Zong et al., 2022 ). Studies have shown that adding 1–2 mg of SB to the diet of Nile tilapia juveniles can significantly improve the activities of TP and transaminase ( Abdel-Latif et al., 2021 ).…”

Lithocholic Acid Alleviates Deoxynivalenol-Induced Inflammation and Oxidative Stress via PPARγ-Mediated Epigenetically Transcriptional Reprogramming in Porcine Intestinal Epithelial Cells

“…Consistent with this result, it has been documented that a complex mycotoxin supplementation in pig feed could markedly reduce H3K27ac genome-wide binding in the pig liver. 58 Notably, the cofactors we focused on in the present study expound the contradicted gene expression profiles in DON/LCA treatments and will benefit further exploration in mycotoxin-induced discrepant transcriptional programming.…”

Chitobiose exhibited a lipid-lowering effect in ob/ob−/− mice via butyric acid enrolled liver–gut crosstalk

“…Moreover, COS 2 and COS 3 were found to promote the growth of intestinal probiotics such as Bifidobacterium and Lactobacillus in ob/ob model mice and significantly increase the abundance of functional microbial communities, such as Akkermansia , Clostridiales , Faecalibaculum , Roseburia , Ruminiclostridium , and Alistipes , which are also known to produce butyric acid. Previous study reported that butyrate had been reported to induce the reduction of lipid accumulation (Zong et al 2023 ). For the intervention mechanism investigation, NaB-induced PPARα activation stimulates fatty acid β oxidation, thus contributing to amelioration of high-fat diet-induced NAFLD in adult rats (Sun et al 2018 ).…”