The nuclear receptor CAR (NR1I3) regulates serum triglyceride levels under conditions of metabolic stress

Maglich, Jodi M.; Lobe, David C.; Moore, John T.

doi:10.1194/jlr.m800226-jlr200

Cited by 98 publications

(98 citation statements)

References 30 publications

(32 reference statements)

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“…CAR and PXR are also increasingly recognized as important regulators of genes involved in lipid and glucose homeostasis (for review: [70,71]. In particular, CAR activation reduces the expression of critical genes involved in fatty acid oxidation [72], bile acid synthesis and gluconeogenesis [73]. Further studies should evaluate the potential role of these regulations in mediating metabolic disruption by phthalates in light of their potential to activate both PXR and CAR.…”

Section: Discussionmentioning

confidence: 99%

Di-(2-ethylhexyl)-phthalate (DEHP) activates the constitutive androstane receptor (CAR): A novel signalling pathway sensitive to phthalates

Eveillard¹,

Mselli-Lakhal²,

Mogha³

et al. 2009

Biochemical Pharmacology

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To cite this version:Alexandre Eveillard, Laïla Mselli-Lakhal, Ariane Mogha, Frédéric Lasserre, Arnaud Polizzi, et al.. Di-(2-ethylhexyl)-phthalate (DEHP) activates the Constitutive Androstane Receptor (CAR): a novel signalling pathway sensitive to phthalates. Biochemical Pharmacology, Elsevier, 2009, 77 (11) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 This finding demonstrates that CAR also represents a transcriptional regulator sensitive to phthalates. CAR-mediated effects of DEHP provide a new rationale for most endpoints of phthalates toxicity described previously, including endocrine disruption, hepatocarcinogenesis and the metabolic syndrome.

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Section: Discussionmentioning

confidence: 99%

Di-(2-ethylhexyl)-phthalate (DEHP) activates the constitutive androstane receptor (CAR): A novel signalling pathway sensitive to phthalates

Eveillard¹,

Mselli-Lakhal²,

Mogha³

et al. 2009

Biochemical Pharmacology

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“…Recent studies have shown that CAR can be naturally activated under certain disease states. For example, CAR appears to be the regulatory factor that increases serum triglyceride levels in diabetic ob/ob mice as this abnormality becomes normal when the Car Ϫ/Ϫ genotype is introduced into the ob/ob mice (19). NADPH-cytochrome P450 oxidoreductase (POR) transfers electron to reduce cytochrome P450, which is essential for P450 to catalyze the oxygenase reaction.…”

Section: Discussionmentioning

confidence: 99%

Dephosphorylation of Threonine 38 Is Required for Nuclear Translocation and Activation of Human Xenobiotic Receptor CAR (NR1I3)

Mutoh

Osabe

Inoue

et al. 2009

Journal of Biological Chemistry

121

136

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Upon activation by therapeutics, the nuclear xenobiotic/ constitutive active/androstane receptor (CAR) regulates various liver functions ranging from drug metabolism and excretion to energy metabolism. CAR can also be a risk factor for developing liver diseases such as hepatocellular carcinoma. Here we have characterized the conserved threonine 38 of human CAR as the primary residue that regulates nuclear translocation and activation of CAR. Protein kinase C phosphorylates threonine 38 located on the ␣-helix spanning from residues 29 -42 that constitutes a part of the first zinc finger and continues into the region between the zinc fingers. Molecular dynamics study has revealed that this phosphorylation may destabilize this helix, thereby inactivating CAR binding to DNA as well as sequestering it in the cytoplasm. We have found, in fact, that helix-stabilizing mutations reversed the effects of phosphorylation. Immunohistochemical study using an anti-phosphothreonine 38 peptide antibody has, in fact, demonstrated that the classic CAR activator phenobarbital dephosphorylates the corresponding threonine 48 of mouse CAR in the cytoplasm of mouse liver and translocates CAR into the nucleus. These results define CAR as a cell signal-regulated constitutive active nuclear receptor. These results also provide phosphorylation/dephosphorylation of the threonine as the primary drug target for CAR activation.

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“…CAR(Ϫ/Ϫ) mice showed defective basal and inducible expression of xenobiotic enzymes and altered responses to drugs (Wei et al, 2000). CAR has been suggested recently to play a role in energy metabolism, ranging from thyroid hormone metabolism (Maglich et al, 2004;Qatanani et al, 2005) to lipogenesis (Roth et al, 2008a,b;Gao et al, 2009;Maglich et al, 2009), gluconeogenesis (Ueda et al, 2002;Kodama et al, 2004;Miao et al, 2006;Gao et al, 2009;Wada et al, 2009), and obesity and diabetes (Dong et al, 2009;Gao et al, 2009). It is unclear whether the effect of CAR on lipogenesis involves the cross-talk with LXRs.…”

Section: Introductionmentioning

confidence: 99%

A Functional Cross-Talk between Liver X Receptor-α and Constitutive Androstane Receptor Links Lipogenesis and Xenobiotic Responses

Zhai

Wada²,

Zhang³

et al. 2010

Mol Pharmacol

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The liver X receptor (LXR) and constitutive androstane receptor (CAR) are two nuclear receptors postulated to have distinct functions. LXR is a sterol sensor that promotes lipogenesis, whereas CAR is a xenosensor that controls xenobiotic responses. Here, we show that LXR␣ and CAR are functionally related in vivo. Loss of CAR increased the expression of lipogenic LXR target genes, leading to increased hepatic triglyceride accumulation, whereas activation of CAR inhibited the expression of LXR target genes and LXR ligand-induced lipogenesis. On the other hand, a combined loss of LXR ␣ and ␤ increased the basal expression of xenobiotic CAR target genes, whereas activation of LXR inhibited the expression of CAR target genes and sensitized mice to xenobiotic toxicants. The mutual suppression between LXR␣ and CAR was also observed in cell culture and reporter gene assays. LXR␣, like CAR, exhibited constitutive activity in the absence of an exogenously added ligand by recruiting nuclear receptor coactivators. Interestingly, although CAR competed with LXR␣ for coactivators, the constitutive activity and recruitment of coactivators was not required for CAR to suppress the activity of LXR␣. In vivo chromatin immunoprecipitation assay showed that cotreatment of a CAR agonist compromised the LXR agonist responsive recruitment of LXR␣ to Srebp-1c, whereas an LXR agonist inhibited the CAR agonist-responsive recruitment of CAR to Cyp2b10. In conclusion, our results have revealed dual functions of LXR␣ and CAR in lipogenesis and xenobiotic responses, establishing a unique role of these two receptors in integrating xenobiotic and endobiotic homeostasis.

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The nuclear receptor CAR (NR1I3) regulates serum triglyceride levels under conditions of metabolic stress

Cited by 98 publications

References 30 publications

Di-(2-ethylhexyl)-phthalate (DEHP) activates the constitutive androstane receptor (CAR): A novel signalling pathway sensitive to phthalates

Di-(2-ethylhexyl)-phthalate (DEHP) activates the constitutive androstane receptor (CAR): A novel signalling pathway sensitive to phthalates

Dephosphorylation of Threonine 38 Is Required for Nuclear Translocation and Activation of Human Xenobiotic Receptor CAR (NR1I3)

A Functional Cross-Talk between Liver X Receptor-α and Constitutive Androstane Receptor Links Lipogenesis and Xenobiotic Responses

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