Orphan Nuclear Receptor RORγ Modulates the Genome-Wide Binding of the Cholesterol Metabolic Genes during Mycotoxin-Induced Liver Injury

Abstract

Maintaining lipid homeostasis is crucial to liver function, the key organ that governs the whole-body energy metabolism. In contrast, lipid dysregulation has been implicated in mycotoxin-induced liver injury, by which the pathophysiological regulation and the molecular components involved remain elusive. Here we focused on the potential roles of orphan nuclear receptor (NR) RORγ in lipid programming, and aimed to explore its action on cholesterol regulation in the liver of mycotoxin-exposed piglets. We found that liver tissues were damaged in the mycotoxin-exposed piglets compared to the healthy controls, revealed by histological analysis, elevated seral ALT, AST and ALP levels, and increased caspase 3/7 activities. Consistent with the transcriptomic finding of down-regulated cholesterol metabolism, we demonstrated that both cholesterol contents and cholesterol biosynthesis/transformation gene expressions in the mycotoxin-exposed livers were reduced, including HMGCS1, FDPS, SQLE, EBP, FDFT1 and VLDLR. Furthermore, we reported that RORγ binds to the cholesterol metabolic genes in porcine hepatocytes using a genome-wide ChIP-seq analysis, whereas mycotoxin decreased the RORγ binding occupancies genome-wide, especially at the cholesterol metabolic pathway. In addition, we revealed the enrichment of co-factors p300 and SRC, the histone marks H3K27ac and H3K4me2, together with RNA Polymerase II (Pol-II) at the locus of HMGCS1 in hepatocytes, which were reduced by mycotoxin-exposure. Our results provide a deep insight into the cholesterol metabolism regulation during mycotoxin-induced liver injury, and propose NRs as therapeutic targets for anti-mycotoxin treatments.

Can Red Yeast (Sporidiobolus pararoseus) Be Used as a Novel Feed Additive for Mycotoxin Binders in Broiler Chickens?

“…In contrast, the main effect of the mycotoxins was the significant effect that they had on alanine aminotransferase (ALT) in the broilers that were serum-fed the contaminated diets. The presence of these enzymes at higher concentrations is a biomarker of liver dysfunction and is thought to indicate damage to the membrane integrity of the liver cells [ 25 , 44 ]. Several studies have demonstrated that mycotoxin exposure results in liver function damage with there being significantly increased ALT levels in the serum [ 25 , 44 , 45 ].…”

“…The presence of these enzymes at higher concentrations is a biomarker of liver dysfunction and is thought to indicate damage to the membrane integrity of the liver cells [ 25 , 44 ]. Several studies have demonstrated that mycotoxin exposure results in liver function damage with there being significantly increased ALT levels in the serum [ 25 , 44 , 45 ]. Hepatocytes with an altered lipid metabolism and signaling pathways may be responsible for these consequences [ 44 ], according to the results of a study of the liver’s relative weight.…”

“…Several studies have demonstrated that mycotoxin exposure results in liver function damage with there being significantly increased ALT levels in the serum [ 25 , 44 , 45 ]. Hepatocytes with an altered lipid metabolism and signaling pathways may be responsible for these consequences [ 44 ], according to the results of a study of the liver’s relative weight. In the same way, the present study was carried out to examine the dependent effects of mycotoxins and to assess the relationship between the broilers’ exposure to mycotoxins and the adsorbent concentrations of AFB1, ZEN, OTA, T-2, and DON in their blood samples.…”

Nuclear Receptor RORα/γ: Exciting Modulators in Metabolic Syndrome and Related Disorders

“…Intriguingly, RORγ is found to share the binding peaks with SREBP2 and determines the SREBP2 recruitments on the target genes. In the in viv o model using piglets, ChIP-seq analysis provides the proof that hepatic RORγ exhibited strong enrichments on the cholesterol biosynthesis genes at the enhancer region ( 60 ). In the liver organoids, RORγ agonists, such as desmosterol and a commercial drug SR0987, displayed drastical restoration of reduced cholesterol content, along with biosynthetic genes caused by a time-restricted feeding ( 61 ).…”

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

“…Owing to that lipid rafts are composed of cholesterol and sphingolipids, maintenance of cholesterol homeostasis is of great importance to ameliorate mycotoxin-induced liver injury as documented [7]. In contrast, mycotoxin exposure can elicit altered cholesterol production and dynamic balance, likely via the modulation of genes involved in cholesterol metabolic processes [8]. This suggests these genes are critical players enrolled in the prevention of mycotoxin damage.…”