Alpha-ketoglutarate suppresses the NF-κB-mediated inflammatory pathway and enhances the PXR-regulated detoxification pathway.
Alpha-ketoglutarate suppresses the NF-κB-mediated inflammatory pathway and enhances the PXR-regulated detoxification pathway.
复制标题
DOI：
10.18632/oncotarget.16875
复制
发表时间：
2017-11-28
期刊：
影响因子：
--
通讯作者：
Yao K
中科院分区：
文献类型：
--
作者：
He L;Li H;Huang N;Zhou X;Tian J;Li T;Wu J;Tian Y;Yin Y;Yao K
α -酮戊二酸（AKG）是维持肠道内稳态的关键营养因子。然而，AKG的相关机制尚不清楚。近年来研究表明，核因子κB （NF-κB）介导的炎症途径与妊娠X受体（PXR）调节的解毒途径相互作用是维持肠道内稳态的一种制衡机制，可防止肠道炎症的发生而导致癌症。本研究采用脂多糖（LPS）刺激仔猪和猪肠上皮细胞- j2模型，研究饲粮中添加AKG对仔猪肠道免疫系统和PXR调控靶点表达的影响。我们发现，LPS诱导NF-κ b介导的炎症通路显著激活，同时肠道营养吸收受损。AKG在体内和体外均增加了细胞内AKG及其代谢物浓度，增强了α -酮戊二酸脱氢酶mRNA的表达。因此，膳食中补充AKG可以逆转LPS诱导的不良反应。我们还发现lps对NF-κB介导的炎症通路有较强的抑制作用，特别是在akg处理的肠道组织中，lps诱导的NF-κB磷酸化被抑制，TNF-α被抑制。有趣的是，尽管AKG不是已知的PXR配体，但AKG在体内和体外调节PXR及其下游靶点（如CYP3As和CYP2Bs）方面具有强大的作用。PXR通路上调的一个潜在机制是通过NF-κB通路下调，进而抑制PXR调控的靶蛋白表达。综上所述，我们的研究结果表明AKG通过调节PXR和NF-κB之间的相互作用来改善肠道免疫系统。我们的发现对预防和治疗新生儿肠道炎症性疾病具有重要意义。
Alpha-ketoglutarate (AKG) is a critical nutritional factor in the maintenance of intestinal homeostasis. However, the relative mechanism of AKG has not been well understood. It was recently shown that the interaction between nuclear factor kappa B (NF-κB)-mediated inflammatory pathway and pregnane X receptor (PXR)-regulated detoxification pathway is a check and balance mechanism for keeping the homeostatic state of the intestine, preventing the onset of intestinal inflammation which may lead to cancer. In the current study we used lipopolysaccharide (LPS)-challenged piglet and intestinal porcine epithelial cells-J2 models to investigate the effects of dietary AKG supplementation on the intestinal immune system and PXR regulated target expression. We found that LPS induced significant activation of the NF-κB-mediated inflammatory pathway with concomitant impairment of intestinal nutrient absorption. AKG administration increased intracellular AKG and its metabolite concentrations and enhanced the mRNA expression of alpha-ketoglutarate dehydrogenase in vivo and in vitro. Thus dietary AKG supplementation reversed the adverse effects induced by LPS. We also found a strong inhibitory effects on the NF-κB-mediated inflammatory pathway, especially, in the AKG-treated intestinal tissues, LPS-induced NF-κB phosphorylation was inhibited and TNF-α was suppressed. Interestingly, AKG has potent effects in regulating the PXR and its downstream targets such as CYP3As and CYP2Bs in vivo and in vitro, although AKG is not a known PXR ligand. One potential mechanism for the up-regulation of the PXR pathway is through the down-regulation of NF-κB pathway which in turn de-represses the PXR-regulated target expression. Taken together, our results suggest that AKG improves intestinal immune system through modulating the interaction between PXR and NF-κB. Our findings have important implications for the prevention and treatment of intestinal inflammatory diseases in neonates.
登录
查看更多内容
影响因子：
3.5
作者：
Hou, Yongqing;Wang, Lei;Wu, Guoyao
通讯作者：
Wu, Guoyao
壳寡糖可减少脂多糖 (LPS) 挑战仔猪中涉及钙敏感受体 (CaSR) 激活的肠道炎症
影响因子：
6.1
作者：
Huang, Bo;Xiao, Dingfu;Yin, Yulong
通讯作者：
Yin, Yulong
Toll样受体4位于高尔基体中，并与肠上皮细胞中的内部脂多糖共定位。
DOI：
10.1084/jem.20011788
发表时间：
2002-03-04
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Hornef MW;Frisan T;Vandewalle A;Normark S;Richter-Dahlfors A
通讯作者：
Richter-Dahlfors A
DOI：
10.1177/1074248415578906
发表时间：
2015-11-01
影响因子：
2.6
作者：
Moon, Jung Yeon;Chang, Byung Chul;Gwak, Hye Sun
通讯作者：
Gwak, Hye Sun
黄芩苷对脂多糖诱导的肠上皮细胞及细胞间紧密连接损伤的保护作用
影响因子：
2.1
作者：
Chen, Jian;Zhang, Ren;Kuang, Zaoyuan
通讯作者：
Kuang, Zaoyuan