The xenobiotic receptors PXR and CAR in liver physiology, an update

Cai, Xinran; Young, Gregory M.; Xie, Wen

doi:10.1016/j.bbadis.2021.166101

Cited by 44 publications

(30 citation statements)

References 98 publications

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“…To this end, it is necessary to conduct bioinformatics analysis on the sequence of the promoter region of miR-3692-5p and predict which transcription factors can bind to the promoter of miR-3692-5p and the possible interaction between FBI-1 and these transcription factors. Moreover, as the body's regulatory center for the metabolism and elimination of exogenous drugs and toxicants, PXR expression in hepatocytes and HCC cells is significantly higher than in other types of tissues (63)(64)(65)(66). It has been confirmed that PXR also plays an important role in the resistance of HCC cells to molecular targeted drugs (67)(68)(69)(70).…”

Section: Discussionmentioning

confidence: 99%

Knockdown of FBI-1 Inhibits the Warburg Effect and Enhances the Sensitivity of Hepatocellular Carcinoma Cells to Molecular Targeted Agents via miR-3692/HIF-1α

Liu¹,

Yang²,

Huang³

et al. 2021

Front. Oncol.

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The transcription suppressor factor FBI-1 (the factor that binds to inducer of short transcripts-1) is an important regulator of hepatocellular carcinoma (HCC). In this work, the results showed that FBI-1 promoted the Warburg effect and enhances the resistance of hepatocellular carcinoma cells to molecular targeted agents. Knockdown of FBI-1 via its small-interfering RNA (siRNA) inhibited the ATP level, lactate productions, glucose uptake or lactate dehydrogenase (LDH) activation of HCC cells. Transfection of siFBI-1 also decreased the expression of the Warburg-effect-related factors: hypoxia-inducible factor-1 alpha (HIF-1α), lactate dehydrogenase A (LDHA), or GLUT1, and the epithelial–mesenchymal transition-related factors, Vimentin or N-cadherin. The positive correlation between the expression of FBI-1 with HIF-1α, LDHA, or GLUT1 was confirmed in HCC tissues. Mechanistically, the miR-30c repressed the expression of HIF-1α by binding to the 3′-untranslated region (3′-UTR) of HIF-1α in a sequence-specific manner, and FBI-1 enhanced the expression of HIF-1α and HIF-1α pathway’s activation by repressing the expression of miR. By modulating the miR-30c/HIF-1α, FBI-1 promoted the Warburg effect or the epithelial–mesenchymal transition of HCC cells and promoted the resistance of HCC cells to molecular targeted agents.

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Section: Discussionmentioning

confidence: 99%

Knockdown of FBI-1 Inhibits the Warburg Effect and Enhances the Sensitivity of Hepatocellular Carcinoma Cells to Molecular Targeted Agents via miR-3692/HIF-1α

Liu¹,

Yang²,

Huang³

et al. 2021

Front. Oncol.

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“…For example, rifampicin interacts with 18 residues of the LBD, forming hydrogen bonds with Ser247, His407, and Gln285, while the HIV reverse transcriptase inhibitor PNU-142721 uses the hydrophobic cage to connect with PXR, through a π–π bond with Phe288 [ 18 ]. Some species-related differences observed in the affinity of PXR ligands could be ascribable to the low homology (73%) of the ligand-binding pocket of PXR between human and mouse [ 21 ]. Consequently, rifampicin shows a high affinity towards human but not murine PXR, while PCN is a potent activator of PXR in mice.…”

Section: Pxr Structure Expression and Activationmentioning

confidence: 99%

The Nuclear Receptor PXR in Chronic Liver Disease

Sayaf

Zanotto

Russo

et al. 2021

Cells

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Pregnane X receptor (PXR), a nuclear receptor known for modulating the transcription of drug metabolizing enzymes and transporters (DMETs), such as cytochrome P450 3A4 and P-glycoprotein, is functionally involved in chronic liver diseases of different etiologies. Furthermore, PXR activity relates to that of other NRs, such as constitutive androstane receptor (CAR), through a crosstalk that in turn orchestrates a complex network of responses. Thus, besides regulating DMETs, PXR signaling is involved in both liver damage progression and repair and in the neoplastic transition to hepatocellular carcinoma. We here summarize the present knowledge about PXR expression and function in chronic liver diseases characterized by different etiologies and clinical outcome, focusing on the molecular pathways involved in PXR activity. Although many molecular details of these finely tuned networks still need to be fully understood, we conclude that PXR and its modulation could represent a promising pharmacological target for the identification of novel therapeutical approaches to chronic liver diseases.

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“…CAR and other nuclear receptors are activated by a wide range of structurally diverse foreign chemicals, including many industrial pollutants and pharmaceuticals (Baldwin and Roling 2009;Chang and Waxman 2006;Hernandez et al 2009;Kobayashi et al 2015;Omiecinski et al 2011). CAR also regulates normal physiological pathways, including hepatic energy homeostasis, cell proliferation and inflammation (Cai et al 2021) and may thereby impact pathophysiological conditions such as fatty liver disease, diabetes, and hepatocellular carcinoma (Cave et al 2016;Dong et al 2009;Phillips et al 2007).…”

Section: Introductionmentioning

confidence: 99%

Impact of neonatal activation of nuclear receptor CAR (Nr1i3) on Cyp2 gene expression in adult mouse liver

Shin

Waxman

2022

Preprint

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Perinatal exposure to environmental chemicals is proposed to reprogram development and alter disease susceptibility later in life. Supporting this, neonatal activation of the nuclear receptor CAR (Nr1i3) by TCPOBOP induces persistent expression of mouse hepatic Cyp2 genes into adulthood, attributed to long-term epigenetic memory of the early life exposure [Hepatology (2012) 56:1499-1509]. Here, we confirm that the same high-dose (15x ED50) neonatal TCPOBOP exposure used in that work induces prolonged (12 weeks) increases in hepatic Cyp2 expression; however, we show that the persistence of expression can be fully explained by the persistence of residual TCPOBOP in liver tissue. When the long-term presence of TCPOBOP in tissue was eliminated by decreasing the neonatal TCPOBOP dose 22-fold (0.67x ED50), strong neonatal increases in hepatic Cyp2 expression were still obtained but did not persist into adulthood. Furthermore, the neonatal ED50-range TCPOBOP exposure did not sensitize mice to a subsequent, low-dose TCPOBOP treatment. In contrast, neonatal treatment with phenobarbital, a short half-life (t1/2=8 h) agonist of CAR and of PXR (Nr1i2), induced high-level neonatal activation of Cyp2 genes and also altered their responsiveness to low-dose phenobarbital exposure at adulthood by either increasing (Cyp2b10) or decreasing (Cyp2c55) expression. Thus, neonatal xenobiotic exposure can reprogram hepatic Cyp2 genes and alter their responsiveness to exposures later in life. These findings highlight the need to carefully consider xenobiotic dose, half-life and persistence in tissue when evaluating the long-term effects of early life environmental chemical exposures.

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The xenobiotic receptors PXR and CAR in liver physiology, an update

Cited by 44 publications

References 98 publications

Knockdown of FBI-1 Inhibits the Warburg Effect and Enhances the Sensitivity of Hepatocellular Carcinoma Cells to Molecular Targeted Agents via miR-3692/HIF-1α

Knockdown of FBI-1 Inhibits the Warburg Effect and Enhances the Sensitivity of Hepatocellular Carcinoma Cells to Molecular Targeted Agents via miR-3692/HIF-1α

The Nuclear Receptor PXR in Chronic Liver Disease

Impact of neonatal activation of nuclear receptor CAR (Nr1i3) on Cyp2 gene expression in adult mouse liver

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