Characterization of a novel PXR isoform with potential dominant-negative properties

Breuker, Cyril; Planque, Chris; Rajabi, Fatemeh; Nault, Jean–Charles; Couchy, Gabrielle; Zucman‐Rossi, Jessica; Evrard, Alexandre; Kantar, Jovana; Chevet, Éric; Bioulac‐Sage, Paulette; Ramos, Jeanne; Assenat, Éric; Joubert, Dominique; Pannequin, Julie; Hollande, Frédéric; Pascussi, Jean Marc

doi:10.1016/j.jhep.2014.04.030

Cited by 16 publications

(19 citation statements)

References 33 publications

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“…Numerous variants of the NR1I2 gene have been described in humans, and at least two NRL1I2 polymorphisms, rs7643645/G and rs2461823, have been associated with increased severity of NAFLD [70]. Another variant has been reported which encodes a short (37 kDa) dominant negative PXR isoform which represses the function of full-length PXR, likely through competition for cofactors such as steroid receptor coactivator 1 (SRC-1) [71]. PXR functions as a sensor for a vast array of exogenous chemical toxicants, coupling cellular metabolic and detoxification programs to respond to an ever-changing environment [72,73].…”

Section: Pregnane X Receptormentioning

confidence: 99%

Nuclear receptors and nonalcoholic fatty liver disease

Cave

Clair

Hardesty

et al. 2016

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

233

204

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Nuclear receptors are transcription factors which sense changing environmental or hormonal signals and effect transcriptional changes to regulate core life functions including growth, development, and reproduction. To support this function, following ligand-activation by xenobiotics, members of subfamily 1 nuclear receptors (NR1s) may heterodimerize with the retinoid X receptor (RXR) to regulate transcription of genes involved in energy and xenobiotic metabolism and inflammation. Several of these receptors including the peroxisome proliferator-activated receptors (PPARs), the pregnane and xenobiotic receptor (PXR), the constitutive androstane receptor (CAR), the liver X receptor (LXR) and the farnesoid X receptor (FXR) are key regulators of the gut:liver:adipose axis and serve to coordinate metabolic responses across organ systems between the fed and fasting states. Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease and may progress to cirrhosis and even hepatocellular carcinoma. NAFLD is associated with inappropriate nuclear receptor function and perturbations along the gut:liver:adipose axis including obesity, increased intestinal permeability with systemic inflammation, abnormal hepatic lipid metabolism, and insulin resistance. Environmental chemicals may compound the problem by directly interacting with nuclear receptors leading to metabolic confusion and the inability to differentiate fed from fasting conditions. This review focuses on the impact of nuclear receptors in the pathogenesis and treatment of NAFLD. Clinical trials including PIVENS and FLINT demonstrate that nuclear receptor targeted therapies may lead to the paradoxical dissociation of steatosis, inflammation, fibrosis, insulin resistance, dyslipidemia and obesity. Novel strategies currently under development (including tissue-specific ligands and dual receptor agonists) may be required to separate the beneficial effects of nuclear receptor activation from unwanted metabolic side effects. The impact of nuclear receptor crosstalk in NAFLD is likely to be profound, but requires further elucidation. This article is part of a Special Issue entitled: Xenobiotic nuclear receptors: New Tricks for An Old Dog, edited by Dr. Wen Xie.

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Section: Pregnane X Receptormentioning

confidence: 99%

Nuclear receptors and nonalcoholic fatty liver disease

Cave

Clair

Hardesty

et al. 2016

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

233

204

View full text Add to dashboard Cite

show abstract

“…PXR, expressed in many tissues but mainly in the liver [ 207 ], is released not only by hepatocytes, but also by Kupffer and stellate cells [ 208 ]. Two polymorphisms of this gene have been associated with augmented severity of NAFLD: rs7643645/G and rs2461823 [ 209 ], whereas a variant encoding a short dominant negative PXR isoform, which inhibits the full-length isoform activity, has been recently described [ 210 ]. PXR regulates various genes involved in xenobiotic and drug metabolism, including enzymes [ 211 ] that play a role in the oxidative metabolism of lipophilic compounds such as steroids, fatty acids, bile acids, drugs, retinoids, and xenobiotics.…”

Section: Nuclear Receptorsmentioning

confidence: 99%

Molecular Pathogenesis of NASH

Caligiuri

Gentilini

Marra

2016

IJMS

166

140

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Nonalcoholic steatohepatitis (NASH) is the main cause of chronic liver disease in the Western world and a major health problem, owing to its close association with obesity, diabetes, and the metabolic syndrome. NASH progression results from numerous events originating within the liver, as well as from signals derived from the adipose tissue and the gastrointestinal tract. In a fraction of NASH patients, disease may progress, eventually leading to advanced fibrosis, cirrhosis and hepatocellular carcinoma. Understanding the mechanisms leading to NASH and its evolution to cirrhosis is critical to identifying effective approaches for the treatment of this condition. In this review, we focus on some of the most recent data reported on the pathogenesis of NASH and its fibrogenic progression, highlighting potential targets for treatment or identification of biomarkers of disease progression.

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“…While low metastatic potential MCF cells expressed PXR.1 but not PXR.2 mRNA (Dotzlaw et al, 1999), high metastatic potential MDA-MB-231 cells expressed higher levels of both PXR.1 and PXR.2 mRNA (Dotzlaw et al, 1999). Very recently, a novel PXR isoform displaying a dominant negative activity has been identified in human hepatocellular carcinoma patients (Breuker et al, 2014). This isoform was found to be regulated by DNA methylation, and associated with outcomes of patients with hepatocellular carcinoma treated by resection.…”

Section: Future Directionsmentioning

confidence: 99%

Pregnane X Receptor and Cancer: Context-Specificity is Key

Pondugula

Pávek

Mani

2016

Nuclear Receptor Research

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Pregnane X receptor (PXR) is an adopted orphan nuclear receptor that is activated by a wide-range of endobiotics and xenobiotics, including chemotherapy drugs. PXR plays a major role in the metabolism and clearance of xenobiotics and endobiotics in liver and intestine via induction of drug-metabolizing enzymes and drug-transporting proteins. However, PXR is expressed in several cancer tissues and the accumulating evidence strongly points to the differential role of PXR in cancer growth and progression as well as in chemotherapy outcome. In cancer cells, besides regulating the gene expression of enzymes and proteins involved in drug metabolism and transport, PXR also regulates other genes involved in proliferation, metastasis, apoptosis, anti-apoptosis, inflammation, and oxidative stress. In this review, we focus on the differential role of PXR in a variety of cancers, including prostate, breast, ovarian, endometrial, and colon. We also discuss the future directions to further understand the differential role of PXR in cancer, and conclude with the need to identify novel selective PXR modulators to target PXR in PXR-expressing cancers.

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Characterization of a novel PXR isoform with potential dominant-negative properties

Cited by 16 publications

References 33 publications

Nuclear receptors and nonalcoholic fatty liver disease

Nuclear receptors and nonalcoholic fatty liver disease

Molecular Pathogenesis of NASH

Pregnane X Receptor and Cancer: Context-Specificity is Key

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