Sodium Butyrate Ameliorates Deoxynivalenol-Induced Oxidative Stress and Inflammation in the Porcine Liver via NR4A2-Mediated Histone Acetylation

Abstract

Mycotoxin-induced liver injury is often accompanied by oxidative stress (OS) and inflammation. This research aimed to explore the potential mechanism of sodium butyrate (NaBu) in modulating hepatic anti-oxidation and anti-inflammation pathways in deoxynivalenol (DON)-exposed piglets. The results show that DON induced liver injury, increased mononuclear cell infiltration, and decreased serum total protein and albumin concentrations. Transcriptomic analysis revealed that reactive oxygen species (ROS) and TNF-α pathways were highly activated upon DON exposure. This is associated with disturbed antioxidant enzymes and increased inflammatory cytokines secretion. Importantly, NaBu effectively reversed the alterations caused by DON. Mechanistically, the ChIP-seq result revealed that NaBu strongly depressed DON-increased enrichment of histone mark H3K27ac at the genes involved in ROS and TNF-α-mediated pathways. Notably, we demonstrated that nuclear receptor NR4A2 was activated by DON and remarkably recovered with the treatment of NaBu. In addition, the enhanced NR4A2 transcriptional binding enrichments at the promoter regions of OS and inflammatory genes were hindered by NaBu in DON-exposed livers. Consistently, elevated H3K9ac and H3K27ac occupancies were also observed at the NR4A2 binding regions. Taken together, our results indicated that a natural antimycotic additive, NaBu, could mitigate hepatic OS and inflammatory responses, possibly via NR4A2-mediated histone acetylation.

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

“…In this regard, the enrichments of histone activation marks H3K27ac and H3K18la were significantly increased by DON. H3K27ac is sensitized to mycotoxin, including DON, thus, the DON-accumulated SRCs recruited histone marks to activate inflammatory gene expressions . Importantly, our study reveals a novel role of LCA in modulating SRC-1/3 via epigenetic mechanisms to reduce mycotoxin-induced inflammation.…”

“…H3K27ac is sensitized to mycotoxin, including DON, thus, the DON-accumulated SRCs recruited histone marks to activate inflammatory gene expressions. 19 Importantly, our study reveals a novel role of LCA in modulating SRC-1/3 via epigenetic mechanisms to reduce mycotoxin-induced inflammation. On the contrary, the downregulated antioxidant genes GPX-4 and HO-1 are more likely attributed to the elevated corepressor NCOR1/2.…”

“…48 LCA plays a protective role in antioxidant activity by regulating antioxidant (SLC7A11 and GPX4) Mycotoxin exposure activates harmful effects via disrupting nuclear receptors (NRs)-dependent inflammation and oxidative stress pathways. 19 PPARγ is a key regulator for ROS accumulation, inflammation, and lipid peroxidation. 49 There have been reports indicating that DON leads to a decrease of PPARγ expression in IPEC-J2.…”

“…Mycotoxin exposure activates harmful effects via disrupting nuclear receptors (NRs)-dependent inflammation and oxidative stress pathways . PPARγ is a key regulator for ROS accumulation, inflammation, and lipid peroxidation .…”

“…15−18 They have also been implicated in the DONinduced inflammation and oxidative stress. 19 Bile acids enter cells via transport proteins located on the membranes of hepatocyte and ileal epithelium, regulating the physiological signaling of NRs and playing a crucial role in immune response, inflammation, and oxidative stress. 20,21 Lithocholic acid (LCA), a monohydroxy bile acid, has been proposed as a potential treatment for intestinal diseases by modulating NR-dependent inflammatory responses.…”