Alpha-ketoglutarate suppresses the NF-κB-mediated inflammatory pathway and enhances the PXR-regulated detoxification pathway.

Liuqin He,Tiejun Li,Yanan Tian,Junquan Tian,Huan Li,Niu Huang,Yulong Yin,Jing Wu,Kang Yao,Xihong Zhou

doi:10.18632/oncotarget.16875

Abstract

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.

Highlights

The gut is a complex organ and its health is maintained through intricate interaction between nutrients, commensal microbiota and host intestinal epithelium [1]
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
Kusunoki et al demonstrated that the p65 subunit of NF-κB interacts with the PXR partner RXRα to regulate cytochrome P450 (CYP450) activity, and this interaction may account for the inhibition of drug metabolism observed in inflammatory states [7]

Summary

Introduction

The gut is a complex organ and its health is maintained through intricate interaction between nutrients, commensal microbiota and host intestinal epithelium [1]. As an organ that constantly comes into contact with the ingested nutrients together with the inevitable toxic substances, numerous commensal bacteria flora [2], the gut epithelium has various detoxification mechanisms involved in many nuclear receptors (NRs). Kusunoki et al demonstrated that the p65 subunit of NF-κB interacts with the PXR partner RXRα to regulate cytochrome P450 (CYP450) activity, and this interaction may account for the inhibition of drug metabolism observed in inflammatory states [7]. This suggest that the bidirectional negative crosstalk between PXR and NF-κB pathway is important for the health of gut epithelium and xenobiotic metabolism [8]

Methods

Results

Conclusion