Nuclear Receptors CAR and PXR Cross Talk with FOXO1 To Regulate Genes That Encode Drug-Metabolizing and Gluconeogenic Enzymes

Pharmacogenetics Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
Molecular and Cellular Biology (Impact Factor: 4.78). 10/2004; 24(18):7931-40. DOI: 10.1128/MCB.24.18.7931-7940.2004
Source: PubMed


The nuclear receptors CAR and PXR activate hepatic genes in response to therapeutic drugs and xenobiotics, leading to the induction of drug-metabolizing enzymes, such as cytochrome P450. Insulin inhibits the ability of FOXO1 to express genes encoding gluconeogenic enzymes. Induction by drugs is known to be decreased by insulin, whereas gluconeogenic activity is often repressed by treatment with certain drugs, such as phenobarbital (PB). Performing cell-based transfection assays with drug-responsive and insulin-responsive enhancers, glutathione S-transferase pull down, RNA interference (RNAi), and mouse primary hepatocytes, we examined the molecular mechanism by which nuclear receptors and FOXO1 could coordinately regulate both enzyme pathways. FOXO1 was found to be a coactivator to CAR- and PXR-mediated transcription. In contrast, CAR and PXR, acting as corepressors, downregulated FOXO1-mediated transcription in the presence of their activators, such as 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) and pregnenolone 16alpha-carbonitrile, respectively. A constitutively active mutant of the insulin-responsive protein kinase Akt, but not the kinase-negative mutant, effectively blocked FOXO1 activity in cell-based assays. Thus, insulin could repress the receptors by activating the Akt-FOXO1 signal, whereas drugs could interfere with FOXO1-mediated transcription by activating CAR and/or PXR. Treatment with TCPOBOP or PB decreased the levels of phosphoenolpyruvate carboxykinase 1 mRNA in mice but not in Car(-/-) mice. We conclude that FOXO1 and the nuclear receptors reciprocally coregulate their target genes, modulating both drug metabolism and gluconeogenesis.

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    • "In mammalian cells, FoxO binds to several nuclear hormone receptors (NHRs), such as constitutive androstane receptor (CAR) and pregnane X receptor (PXR), to regulate CYP450 expression (Kodama et al., 2004). The functional ecdysone receptor is composed of two NHRs, Ecdysone Receptor (EcR) and Ultraspiracle (Usp). "
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    ABSTRACT: Despite their fundamental importance for body size regulation, the mechanisms that stop growth are poorly understood. In Drosophila melanogaster, growth ceases in response to a peak of the molting hormone ecdysone that coincides with a nutrition-dependent checkpoint, critical weight. Previous studies indicate that insulin/insulin-like growth factor signaling (IIS)/Target of Rapamycin (TOR) signaling in the prothoracic glands (PGs) regulates ecdysone biosynthesis and critical weight. Here we elucidate a mechanism through which this occurs. We show that Forkhead Box class O (FoxO), a negative regulator of IIS/TOR, directly interacts with Ultraspiracle (Usp), part of the ecdysone receptor. While overexpressing FoxO in the PGs delays ecdysone biosynthesis and critical weight, disrupting FoxO-Usp binding reduces these delays. Further, feeding ecdysone to larvae eliminates the effects of critical weight. Thus, nutrition controls ecdysone biosynthesis partially via FoxO-Usp prior to critical weight, ensuring that growth only stops once larvae have achieved a target nutritional status.
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    • "PXR expressed primarily in the liver, intestine and kidney is a xenobiotic sensing nuclear receptor, involved in detoxification of drugs and other foreign chemicals [33]. While previous studies have established functional links between glucose homeostasis and PXR, the in vivo significance of PXR function in obesity and metabolic syndrome has not been fully explored [34] [35] [36]. The sequences of human and mouse PXRs share nearly 77% amino acid identity across the C-terminal ligand binding domain (LBD), 96% amino acid identity in the N-terminal DNA-binding domain, and the two PXRs display similar tissue-specific expression patterns [33]. "
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    • "Recently, CAR has received renewed attention as a molecular target for the treatment of metabolic diseases, because of its key role in energy homeostasis such as thyroid hormone metabolism (Maglich et al. 2004; Qatanani et al. 2005), glucogenesis (Ueda et al. 2002; Kodama et al. 2004; Miao et al. 2006), and lipogenesis (Roth et al. 2008a,b). Furthermore, in vivo studies using ob/ob mice and high-fat diet-fed mice have shown that CAR activation suppresses glucose production, stimulates glucose uptake, improves glucose tolerance and insulin sensitivity, and prevents obesity (Gao et al. 2009; Dong et al. 2009). "
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