Nur77 Coordinately Regulates Expression of Genes Linked to Glucose Metabolism in Skeletal Muscle

Chao, Lily C.; Zhang, Zidong; Pei, Liming; Saito, Tsugumichi; Tontonoz, Peter; Pilch, Paul F.

doi:10.1210/me.2007-0169

Cited by 154 publications

(181 citation statements)

References 49 publications

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“…Nr4a family members were shown to exert transcriptional activity in a ligand-independent manner (6), and they have been implicated in the regulation of glucose metabolism, apoptosis, and inflammation, as well as the differentiation of monocytes and T cells (7)(8)(9)(10)(11)(12)(13)(14).…”

mentioning

confidence: 99%

The Nuclear Receptor Nr4a1 Mediates Anti-Inflammatory Effects of Apoptotic Cells

Ipseiz

Uderhardt

Scholtysek

et al. 2014

The Journal of Immunology

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Uptake of apoptotic cells (ACs) by macrophages ensures the nonimmunogenic clearance of dying cells, as well as the maintenance of self-tolerance to AC-derived autoantigens. Upon ingestion, ACs exert an inhibitory influence on the inflammatory signaling within the phagocyte. However, the molecular signals that mediate these immune-modulatory properties of ACs are incompletely understood. In this article, we show that the phagocytosis of apoptotic thymocytes was enhanced in tissue-resident macrophages where this process resulted in the inhibition of NF-κB signaling and repression of inflammatory cytokines, such as IL-12. In parallel, ACs induced a robust expression of a panel of immediate early genes, which included the Nr4a subfamily of nuclear receptors. Notably, deletion of Nr4a1 interfered with the anti-inflammatory effects of ACs in macrophages and restored both NF-κB signaling and IL-12 expression. Accordingly, Nr4a1 mediated the anti-inflammatory properties of ACs in vivo and was required for maintenance of self-tolerance in the murine model of pristane-induced lupus. Thus, our data point toward a key role for Nr4a1 as regulator of the immune response to ACs and of the maintenance of tolerance to “dying self.”

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mentioning

confidence: 99%

The Nuclear Receptor Nr4a1 Mediates Anti-Inflammatory Effects of Apoptotic Cells

Ipseiz

Uderhardt

Scholtysek

et al. 2014

The Journal of Immunology

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“…18 Both LXRa and LXRb increase target gene transcription by binding to DNA sequence motifs composed of two hexameric nucleotide direct repeats separated by four bases (DR-4). 19 Although in the earlier study, LXRa and NOR-1 were separately shown to participate in regulating genes involved in metabolic fuel usage, [7][8][9][10]16,20 our current studies in adipocytes identify a direct involvement of LXRa to regulate NOR-1 gene transcription through a DR-4 element in the NOR-1 promoter.…”

Section: Introductionmentioning

confidence: 52%

“…NR4A receptors were shown to contribute to the cAMP-dependent transcription of glucose-6-phosphatase in the liver, a key step in hepatic gluconeogenesis, 10 as well as to the regulation of genes involved in glucose and oxidative metabolism in skeletal muscle. 8,26 In adipose tissue, NR4As have been linked to the recruitment of GLUT4 receptors to the plasma membrane, resulting in improved insulin sensitivity, 7 and in brown adipocytes, NOR-1 contributes to the cAMP-dependent transcription of the Ucp1 gene, the induction of which is necessary for sustained adaptive thermogenesis. 9 Our finding of another transcriptional regulatory pathway to regulate NR4As, and the NOR-1 gene in particular in response to LXR, underscores the fact that we still do not know the full extent to which there is cross-talk between the nuclear receptor families to modulate each other's expression.…”

Section: Discussionmentioning

confidence: 99%

“…[2][3][4][5][6] More recently, these receptors have been shown to function in the regulation of important genes involved in metabolic homeostasis in the liver, adipose and muscle. [7][8][9][10] From structural considerations, the NR4As do not appear to contain a functional ligand-binding pocket, and thus are ligand-independent transcriptional regulators. 11,12 Of the several stimuli known to increase the expression of the NR4As, many do so through elevations in cyclic adenosine monophosphate (cAMP) levels.…”

Section: Introductionmentioning

confidence: 99%

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Liver X receptor is a regulator of orphan nuclear receptor NOR-1 gene transcription in adipocytes

Kumar

Liu

et al. 2009

Int J Obes

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Objective: The liver X receptors (LXRs) are ligand-activated nuclear transcription factors that have been shown to play major roles in lipid, glucose and cholesterol metabolism. Recently, members of the NR4A orphan nuclear receptor family have also been shown to regulate the expression of important genes in metabolically active tissues such as liver, adipose and skeletal muscle. Here, we investigated the role of LXRs to regulate the expression of the nuclear receptor NOR-1 (neuron-derived orphan receptor-1) in adipocytes. Approach: White and brown adipose tissues from wild-type, LXRaÀ/À-and LXRa:b-deficient mice were collected from animals at room temperature or following cold exposure to measure NOR-1 mRNA. The expression of NOR-1 and its promoter activity in response to LXR ligands were determined in cultured primary brown adipocytes or mouse embryo fibroblasts derived from wildtype or LXRaÀ/À mice differentiated into adipocytes. Results: In LXRaÀ/À-and LXRa:b-deficient adipocytes, basal levels of NOR-1 were significantly reduced while retaining an equivalent proportional induction by b-adrenergic agonists. This reduced basal expression of NOR-1 in adipose tissue from LXR-deficient mice is a cell-autonomous event as it was also preserved in adipocytes differentiated from mouse embryo fibroblasts derived from these mice. In cultured primary brown adipocytes or cell lines, the expression of NOR-1 increased in response to an LXR agonist. A DNA sequence element (DR-4) capable of binding LXRs was found at À997 bp of the NOR-1 promoter, which was shown to be functional by promoter reporter gene activity, gel shift and chromatin immunoprecipitation assays. Conclusion: These data describe a new role for LXR to regulate NOR-1 gene expression in adipocytes and demonstrate that these two nuclear receptors have an interdependent regulatory relationship, in addition to each being involved in the control of metabolic fuel usage.

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“…Moreover, we found that NR4A1 overexpression inhibited adipogenesis in 3T3‐L1 pre‐adipocytes. In vivo, it has been reported that NR4A1 had the effects on glucose and lipid metabolism in liver 31, 32 and muscles 30, 33. Studies have shown that NR4A1 knockout mice fed with high‐fat diet were more likely to develop obesity compared to WT mice 23.…”

Section: Discussionmentioning

confidence: 99%

NR4A1 retards adipocyte differentiation or maturation via enhancing GATA2 and p53 expression

Qin

Yang

et al. 2018

J Cellular Molecular Medi

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Nuclear receptor subfamily 4 group A member 1 (NR4A1) is an orphan nuclear receptor with diverse functions. It has been reported that NR4A1, as a transcriptional activator, is implicated in glucose and lipid metabolism. The aim of this study was to investigate the regulatory role of NR4A1 in adipogenesis and explore the underlying mechanisms. Quantitative real‐time PCR and Western blotting were used to analyse the expression of genes involved in synthesis and mobilization of fats in vivo and in vitro. Dual‐luciferase reporter assay was conducted to study the regulatory mechanisms of NR4A1. Our data from in vivo study confirmed that NR4A1 knockout (KO) mice fed with high‐fat diet were more prone to obesity, and gene expression levels of PPARγ and FAS were increased in KO mice compared to controls; our data from in vitro study showed that NR4A1 overexpression in 3T3‐L1 pre‐adipocytes inhibited adipogenesis. Moreover, NR4A1 enhanced GATA binding protein 2 (GATA2) expression, which in turn inhibited peroxisome proliferator‐activated receptor γ (PPARγ); NR4A1 inhibited sterol regulatory element binding transcription factor 1 (SREBP1) and its downstream gene fatty acid synthase (FAS) by up‐regulating p53. NR4A1 inhibits the differentiation and lipid accumulation of adipocytes by enhancing the expression of GATA2 and p53.

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Nur77 Coordinately Regulates Expression of Genes Linked to Glucose Metabolism in Skeletal Muscle

Cited by 154 publications

References 49 publications

The Nuclear Receptor Nr4a1 Mediates Anti-Inflammatory Effects of Apoptotic Cells

The Nuclear Receptor Nr4a1 Mediates Anti-Inflammatory Effects of Apoptotic Cells

Liver X receptor is a regulator of orphan nuclear receptor NOR-1 gene transcription in adipocytes

NR4A1 retards adipocyte differentiation or maturation via enhancing GATA2 and p53 expression

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