Functions of pregnane X receptor in self-detoxification

He, Liuqin; Zhou, Xin; Huang, Niu; Li, Huan; Li, Tiejun; Yao, Kang; Yan, Tian; Hu, Chien‐An Andy; Yin, Yulong

doi:10.1007/s00726-017-2435-0

Cited by 18 publications

(8 citation statements)

References 82 publications

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“…Chen et al reported that AKG intervention in mice reduces body weight and affects the intestinal innate immunity via alterations of gut microbiota [20]. It is interesting that studies have also identified that AKG treatment can inhibit the NF- κ B-mediated inflammatory pathway, thereby enhancing gut immunity and promoting self-detoxification systems [29, 33]. It has also been validated that AKG intervention can enhance the expression of inflammatory cytokines [29].…”

Section: Discussionmentioning

confidence: 99%

Intervention withα-Ketoglutarate Ameliorates Colitis-Related Colorectal Carcinoma via Modulation of the Gut Microbiome

Zhao

et al. 2019

BioMed Research International

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The intestinal microbiome plays a crucial role in promoting intestinal health, and perturbations to its constitution may result in chronic intestinal inflammation and lead to colorectal cancer (CRC). α-Ketoglutarate is an important intermediary in the NF-κB-mediated inflammatory pathway that maintains intestinal homeostasis and prevents initiation of intestinal inflammation, a known precursor to carcinoma development. The objective of this study was to assess the potential protective effects of α-ketoglutarate intervention against CRC development, which may arise due to its known anti-inflammatory and antitumour effects. CRC was induced in C57BL/6 mice using azoxymethane (AOM) and dextran sulfate sodium (DSS). Tumour frequency, histological rating, and colonic microbiota were assessed in colonic samples. The findings demonstrated that α-ketoglutarate offered significant protection against CRC development in mice. Furthermore, α-ketoglutarate also exhibited immunomodulatory effects mediated via downregulation of interleukin (IL)-6, IL-22, tumour necrosis factor (TNF)-α, and IL-1β cytokines. Finally, intervention with α-ketoglutarate tended to minimise the frequency of opportunistic pathogens (Escherichia and Enterococcus) while increasing the populations of Akkermansia, Butyricicoccus, Clostridium, and Ruminococcus. Taken together, our findings show that dietary α-ketoglutarate intervention may protect against inflammation-related CRC.

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Section: Discussionmentioning

confidence: 99%

Intervention withα-Ketoglutarate Ameliorates Colitis-Related Colorectal Carcinoma via Modulation of the Gut Microbiome

Zhao

et al. 2019

BioMed Research International

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“…Recently, Chen et al (2015) reported that AKG lowered body weight and affected intestinal innate immunity through influencing intestinal microbiota in mice [ 27 ]. Of note, our group also found that AKG could suppress NF-κB-mediated inflammatory pathway and enhance the PXR-regulated detoxification pathway to improve intestinal immune and self-detoxification system [ 24 , 28 ]. It is further confirmed by our study that AKG as a precursor for the biosynthesis of glutamate and glutamine, inproved the secretion and expression of inflammatory cytokines in response to LPS stimulation, thereby increasing intestinal immunity.…”

Section: Discussionmentioning

confidence: 99%

Administration of alpha-ketoglutarate improves epithelial restitution under stress injury in early-weaning piglets

Zhou

Huang

et al. 2017

Oncotarget

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Alpha-ketoglutarate (AKG) is an important cellular metabolite that participates in energy production and amino acid metabolism. However, the protective effects and mechanism of AKG on mucosal lesions have not been well understood. This study was conducted to investigate the effects of dietary AKG supplementation on epithelial restitution in early-weaning piglets under Escherichia coli lipopolysaccharide (LPS) induction. A total of 32 weaned piglets were used in a 2 × 2 factorial design; the major factors were dietary treatment (basal diet or AKG diet) and inflammatory challenge (LPS or saline). The results showed that AKG supplementation improved the growth performance and intestinal morphology in the LPS-induced early-weaning piglets. Compared with the basal diet, the AKG diet remarkably decreased the concentration and mRNA expression of intestinal inflammatory cytokines (IL-1β, IL-6, and IL-12) in the LPS-induced piglets. Moreover, AKG administration upregulated the mRNA expression of nutrient-sensing transporters (GLUT-2, SGLT-1, PEPT-1, I-FABP2) in the small intestine of both saline- and LPS-treated piglets, and improved the distribution and expression of tight-junction genes andproteins (ZO-1, Occludin, Claudins, E-cadherin). Collectively, our findings indicate that AKG has the potential to alleviate intestinal inflammatory response and improve epithelial restitution and nutrient-sensing ability under stress injury in early-weaning piglets, and it also provides an experimental basis for enteral use of AKG in swine production and clinical application to prevent intestinal epithelial damage.

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“…The corresponding protein band was thereafter subjected to LC-MS/MS assay. After elimination of false-positives presenting in controls, this protein was identified as PXR, a key regulator of the detoxification of xeno- and endobiotics 23 (Fig. 4a ).…”

Section: Resultsmentioning

confidence: 99%

Poly(ADP-ribosyl)ated PXR is a critical regulator of acetaminophen-induced hepatotoxicity

Wang

Zhang

et al. 2018

Cell Death Dis

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Acetaminophen (APAP) overdose is the most frequent cause of acute liver failure and remains a critical problem in medicine. PARP1-dependent poly(ADPribosyl)ation is a key mediator of cellular stress responses and functions in multiple physiological and pathological processes. However, whether it is involved in the process of APAP metabolism remains elusive. In this study, we find that PARP1 is activated in mouse livers after APAP overdose. Pharmacological or genetic manipulations of PARP1 are sufficient to suppress the APAP-induced hepatic toxicity and injury, as well as reduced APAP metabolism. Mechanistically, we identify pregnane X receptor (PXR) as a substrate of PARP1-mediated poly(ADP-ribosyl)ation. The poly(ADP-ribosyl)ation of PXR in ligand-binding domain activates PXR competitively and solidly, facilitates its recruitment to target gene CYP3A11 promoter, and promotes CYP3A11 gene transcription, thus resulting in increases of APAP pro-toxic metabolism. Additionally, PXR silence antagonizes the effects of PARP1 on APAP-induced hepatotoxicity. These results identifies poly(ADP-ribosyl)ation of PXR by PARP1 as a key step in APAP-induced liver injury. We propose that inhibition of PARP1-dependent poly(ADP-ribosyl)ation might represent a novel approach for the treatment of drug-induced hepatotoxicity.

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Functions of pregnane X receptor in self-detoxification

Cited by 18 publications

References 82 publications

Intervention withα-Ketoglutarate Ameliorates Colitis-Related Colorectal Carcinoma via Modulation of the Gut Microbiome

Intervention withα-Ketoglutarate Ameliorates Colitis-Related Colorectal Carcinoma via Modulation of the Gut Microbiome

Administration of alpha-ketoglutarate improves epithelial restitution under stress injury in early-weaning piglets

Poly(ADP-ribosyl)ated PXR is a critical regulator of acetaminophen-induced hepatotoxicity

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