A high-concentrate diet provokes inflammatory responses by downregulating Forkhead box protein A2 (FOXA2) through epigenetic modifications in the liver of dairy cows
A high-concentrate diet provokes inflammatory responses by downregulating Forkhead box protein A2 (FOXA2) through epigenetic modifications in the liver of dairy cows
复制标题
高浓度饮食通过奶牛肝脏的表观遗传修饰下调叉头盒蛋白 A2 (FOXA2)，从而引发炎症反应
DOI：
10.1016/j.gene.2022.146703
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发表时间：
2022
期刊：
影响因子：
3.5
通讯作者：
Xiangzhen Shen
中科院分区：
文献类型：
--
作者：
Wan Xie;Yang Xue;Hongzhu Zhang;Yan Wang;Meijuan Meng;Guangjun Chang;Xiangzhen Shen
•高精料饲粮激活了奶牛肝脏的NF-κB和MAPK促炎信号通路，引发了奶牛肝脏的炎症反应。•高精料日粮下调奶牛肝脏FOXA2表达。•表观遗传机制有助于FOXA2的抑制。•HDAC3和TET1参与FOXA2的表观遗传修饰。据报道，高精料日粮可促进奶牛的炎症反应。本研究旨在阐明高精饲料（HC）对肝脏叉头盒蛋白A2 （FOXA2）表达的影响，揭示肝脏炎症反应的分子机制。结果表明，HC饲粮降低了瘤胃液pH，提高了外周血血浆中SAA3、IL-1α和IL-8的分泌，降低了IL-10的分泌。与低精（LC）组相比，HC组奶牛肝脏中髓过氧化物酶（MPO）浓度较高。HC组肝脏急性期蛋白（HP、SAA3、LBP）、促炎因子（TNFα、IL-1α、IL-1β、IL-8）、TLR4、MyD88、TRAF6、TRIF、IκBα、p65、p38、JNK1 mRNA相对表达上调，IL-10相对表达下调。与LC组相比，HC组TLR4、TNFα蛋白丰度和NF-κB （i -κB α和p65）、MAPK （p38和JNK）通路相关蛋白磷酸化水平均显著升高。HC组FOXA2 mRNA和蛋白丰度均下调。进一步的表观遗传分析结果表明，染色质压缩和DNA高甲基化有助于抑制FOXA2的表达，其中去甲基化酶10 - 11易位1 （TET1）和组蛋白去乙酰化酶3 （HDAC3）可能参与其中。综上所述，这些研究结果表明，高精料日粮引发了奶牛肝脏炎症级联反应，并通过表观遗传修饰下调了FOXA2。
• A high-concentrate diet activated NF-κB and MAPK proinflammatory signaling pathways and triggered the inflammatory responses in the liver of dairy cows. • A high-concentrate diet downregulated hepatic FOXA2 expression in dairy cows. • Epigenetic mechanisms contributed to the suppression of FOXA2 . • HDAC3 and TET1 were involved in the epigenetic modifications of FOXA2 . 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.