A high-concentrate diet provokes inflammatory responses by downregulating Forkhead box protein A2 (FOXA2) through epigenetic modifications in the liver of dairy cows

Abstract

A high-concentrate diet has been reported to promote an inflammatory response in dairy cows. The purpose of this study was to clarify the effect of the high-concentrate (HC) diet on hepatic Forkhead box protein A2 (FOXA2) expression and uncover the molecular mechanisms in inflammatory responses in the liver. The results showed that the HC diet reduced the ruminal fluid pH and elevated the secretion of SAA3, IL-1α, and IL-8 and reduced that of IL-10 in peripheral blood plasma. Compared with the low-concentrate (LC) group, the concentration of myeloperoxidase (MPO) was higher in the liver of dairy cows in the HC group. In addition, the relative mRNA expression of acute phase proteins (HP, SAA3, and LBP), proinflammatory cytokines (TNFα, IL-1α, IL-1β, IL-8), TLR4, MyD88, TRAF6, TRIF, IκBα, p65, p38 and JNK1 was upregulated and that of IL-10 was downregulated in the liver of the HC group. Consistently, the protein abundance of TLR4, TNFα and phosphorylation of proteins involved in NF-κB (IκBα and p65) and MAPK (p38 and JNK) pathways were significantly increased in the HC group compared with the LC group. And both the mRNA and protein abundance of FOXA2 were downregulated in the HC group. Further epigenetic analysis results demonstrated that chromatin compaction and DNA hypermethylation contributed to inhibiting FOXA2 expression, in which the demethylase ten-eleven translocation 1 (TET1) and histone deacetylase 3 (HDAC3) might participate. Overall, these findings demonstrated that the high-concentrate diet triggered inflammatory cascades and downregulated FOXA2 by epigenetic modifications in the liver of dairy cows.