scholarly journals Orphan Nuclear Receptor ERRγ Is a Transcriptional Regulator of CB1 Receptor-Mediated TFR2 Gene Expression in Hepatocytes

2021 ◽  
Vol 22 (11) ◽  
pp. 6021
Author(s):  
Bo-Eun Kim ◽  
Byungyoon Choi ◽  
Woo-Ram Park ◽  
Yu-Ji Kim ◽  
In-Young Kim ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcriptional Regulation ◽  
Nuclear Receptor ◽  
Gene Transcription ◽  
Cannabinoid Receptor ◽  
Gene Promoter ◽  
Cb1 Receptor ◽  
Orphan Nuclear Receptor ◽  
Endocrine Control ◽  
Hepatic Iron Overload

Orphan nuclear receptor estrogen-related receptor γ (ERRγ) is an important transcription factor modulating gene transcription involved in endocrine control of liver metabolism. Transferrin receptor 2 (TFR2), a carrier protein for transferrin, is involved in hepatic iron overload in alcoholic liver disease (ALD). However, TFR2 gene transcriptional regulation in hepatocytes remains largely unknown. In this study, we described a detailed molecular mechanism of hepatic TFR2 gene expression involving ERRγ in response to an endocannabinoid 2-arachidonoylglycerol (2-AG). Treatment with 2-AG and arachidonyl-2′-chloroethylamide, a selective cannabinoid receptor type 1 (CB1) receptor agonist, increased ERRγ and TFR2 expression in hepatocytes. Overexpression of ERRγ was sufficient to induce TFR2 expression in both human and mouse hepatocytes. In addition, ERRγ knockdown significantly decreased 2-AG or alcohol-mediated TFR2 gene expression in cultured hepatocytes and mouse livers. Finally, deletion and mutation analysis of the TFR2 gene promoter demonstrated that ERRγ directly modulated TFR2 gene transcription via binding to an ERR-response element. This was further confirmed by chromatin immunoprecipitation assay. Taken together, these results reveal a previously unrecognized role of ERRγ in the transcriptional regulation of TFR2 gene expression in response to alcohol.

scholarly journals The Orphan Nuclear Receptor ERRγ Regulates Hepatic CB1 Receptor-Mediated Fibroblast Growth Factor 21 Gene Expression

PLoS ONE ◽  
2016 ◽  
Vol 11 (7) ◽  
pp. e0159425 ◽  
Author(s):  
Yoon Seok Jung ◽  
Ji-Min Lee ◽  
Don-Kyu Kim ◽  
Yong-Soo Lee ◽  
Ki-Sun Kim ◽  
...  
Keyword(s):  
Gene Expression ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Nuclear Receptor ◽  
Cb1 Receptor ◽  
Fibroblast Growth Factor 21 ◽  
Orphan Nuclear Receptor ◽  
Fibroblast Growth

scholarly journals Orphan nuclear receptor oestrogen-related receptor γ (ERRγ) plays a key role in hepatic cannabinoid receptor type 1-mediated induction of CYP7A1 gene expression

2015 ◽  
Vol 470 (2) ◽  
pp. 181-193 ◽  
Author(s):  
Yaochen Zhang ◽  
Don-Kyu Kim ◽  
Ji-Min Lee ◽  
Seung Bum Park ◽  
Won-IL Jeong ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bile Acid ◽  
Nuclear Receptor ◽  
Cannabinoid Receptor ◽  
Inverse Agonist ◽  
Receptor Type ◽  
Orphan Nuclear Receptor ◽  
Transcription Regulator ◽  
Estrogen Related Receptor

ERRγ is a novel transcription regulator of CYP7A1 (cholesterol 7α-hydroxylase). An ERRγ (Estrogen-related receptor γ) inverse agonist modulates bile acid homoeostasis via regulation of CYP7A1 gene expression.

scholarly journals Orphan Nuclear Receptor ERRγ Is a Novel Transcriptional Regulator of IL-6 Mediated Hepatic BMP6 Gene Expression in Mice

2020 ◽  
Vol 21 (19) ◽  
pp. 7148
Author(s):  
Kamalakannan Radhakrishnan ◽  
Yong-Hoon Kim ◽  
Yoon Seok Jung ◽  
Jina Kim ◽  
Don-Kyu Kim ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcriptional Regulation ◽  
Molecular Mechanism ◽  
Nuclear Receptor ◽  
Iron Homeostasis ◽  
Luciferase Reporter ◽  
Orphan Nuclear Receptor ◽  
Knock Out

Bone morphogenetic protein 6 (BMP6) is a multifunctional growth factor involved in organ development and homeostasis. BMP6 controls expression of the liver hormone, hepcidin, and thereby plays a crucial role in regulating iron homeostasis. BMP6 gene transcriptional regulation in liver is largely unknown, but would be of great help to externally modulate iron load in pathologic conditions. Here, we describe a detailed molecular mechanism of hepatic BMP6 gene expression by an orphan nuclear receptor, estrogen-related receptor γ (ERRγ), in response to the pro-inflammatory cytokine interleukin 6 (IL-6). Recombinant IL-6 treatment increases hepatic ERRγ and BMP6 expression. Overexpression of ERRγ is sufficient to increase BMP6 gene expression in hepatocytes, suggesting that IL-6 is upstream of ERRγ. In line, knock-down of ERRγ in cell lines or a hepatocyte specific knock-out of ERRγ in mice significantly decreases IL-6 mediated BMP6 expression. Promoter studies show that ERRγ directly binds to the ERR response element (ERRE) in the mouse BMP6 gene promoter and positively regulates BMP6 gene transcription in IL-6 treatment conditions, which is further confirmed by ERRE mutated mBMP6-luciferase reporter assays. Finally, an inverse agonist of ERRγ, GSK5182, markedly inhibits IL-6 induced hepatic BMP6 expression in vitro and in vivo. Taken together, these results reveal a novel molecular mechanism on ERRγ mediated transcriptional regulation of hepatic BMP6 gene expression in response to IL-6.

scholarly journals Transcriptional Regulation of Apolipoprotein C-III Gene Expression by the Orphan Nuclear Receptor RORα

2000 ◽  
Vol 276 (4) ◽  
pp. 2865-2871 ◽  
Author(s):  
Eric Raspé ◽  
Hélène Duez ◽  
Phillippe Gervois ◽  
Catherine Fiévet ◽  
Jean-Charles Fruchart ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcriptional Regulation ◽  
Nuclear Receptor ◽  
Orphan Nuclear Receptor ◽  
Apolipoprotein C

scholarly journals Coregulatory protein–orphan nuclear receptor interactions in the human adrenal cortex

2005 ◽  
Vol 186 (1) ◽  
pp. 33-42 ◽  
Author(s):  
Sinead N Kelly ◽  
T Joseph McKenna ◽  
Leonie S Young
Keyword(s):  
Transcriptional Regulation ◽  
Adrenal Cortex ◽  
Nuclear Receptor ◽  
Tumour Cell Line ◽  
Zona Fasciculata ◽  
Orphan Nuclear Receptor ◽  
Response Element ◽  
Coregulatory Proteins ◽  
Coregulatory Protein ◽  
In Cells

The capacity of the adrenal to produce steroids is controlled in part through the transcriptional regulation of steroid enzymes. The orphan nuclear receptor steroidogenic factor 1 (SF-1) is central to the transcriptional regulation of all steroid hydroxylase enzymes, whereas nur77 can preferentially regulate steroid enzyme genes relevant to cortisol production. We hypothesised that, in the presence of secretagogues, SF-1 and nur77 may differentially interact with coregulatory proteins in the human adrenal cortex. Both coregulatory proteins, steroid receptor coactivator (SRC-1) and silencing mediator for retinoid and thyroid hormones (SMRT), were found to be expressed in the zona fasciculata and reticularis in the human adrenal cortex, but were largely absent from the zona glomerulosa. Both coregulatory proteins were colocalised with SF-1 and nur77. In the H295R adrenal tumour cell line, SF-1 and nur77 transcripts were increased in cells in the presence of forskolin, whereas nur77 mRNA was also induced with angiotensin II (AII). The coactivator SRC-1 mRNA was increased in the presence of both forskolin and AII. Forskolin induced recruitment of SRC-1 to the SF-1 response element and induced SRC-1–SF-1 interactions, whereas AII increased recruitment of SRC-1 to the nur77 response element and induced SRC-1–nur77 interactions. The corepressor SMRT interacted with SF-1 in the presence of AII and with nur77 in cells treated with forskolin. Orphan nuclear receptor–coregulatory protein interactions may have consequences for the regulation of key steroidogenic enzymes in the human adrenal cortex.

scholarly journals TR4 orphan nuclear receptor functions as an apoptosis modulator via regulation of Bcl-2 gene expression

2007 ◽  
Vol 361 (2) ◽  
pp. 323-328 ◽  
Author(s):  
Eungseok Kim ◽  
Wen-Lung Ma ◽  
Din-Lii Lin ◽  
Shigeki Inui ◽  
Yuh-Ling Chen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nuclear Receptor ◽  
Orphan Nuclear Receptor

LH Induces Orphan Nuclear Receptor Nur77 Gene Expression in Testicular Leydig Cells

Endocrinology ◽  
2001 ◽  
Vol 142 (12) ◽  
pp. 5116-5123 ◽  
Author(s):  
Kwang-Hoon Song ◽  
Jae-Il Park ◽  
Mi-Ock Lee ◽  
Jaemog Soh ◽  
Keesook Lee ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nuclear Receptor ◽  
Leydig Cells ◽  
Orphan Nuclear Receptor

A pleiotropic element in the medium-chain acyl coenzyme A dehydrogenase gene promoter mediates transcriptional regulation by multiple nuclear receptor transcription factors and defines novel receptor-DNA binding motifs

1994 ◽  
Vol 14 (7) ◽  
pp. 4360-4372
Author(s):  
M E Carter ◽  
T Gulick ◽  
D D Moore ◽  
D P Kelly
Keyword(s):  
Transcriptional Regulation ◽  
Nuclear Receptor ◽  
Receptor Binding ◽  
Gene Promoter ◽  
Response Element ◽  
Binding Motifs ◽  
Receptor Response ◽  
Dehydrogenase Gene ◽  
Chain Acyl ◽  
Acyl Coenzyme A

We previously identified a complex regulatory element in the medium-chain acyl coenzyme A dehydrogenase gene promoter that confers transcriptional regulation by the retinoid receptors RAR and RXR and the orphan nuclear receptor HNF-4. In this study we demonstrate a trans-repressing regulatory function for the orphan receptor COUP-TF at this same nuclear receptor response element (NRRE-1). The transcriptional regulatory properties and receptor binding sequences of each nuclear receptor response element within NRRE-1 are also characterized. NRRE-1 consists of four potential nuclear hormone receptor hexamer binding sites, arranged as [<--1-(n)s-2-->-3-->(n)4<--4], three of which are used in alternative pairwise binding by COUP-TF and HNF-4 homodimers and by RAR-RXR heterodimers, as demonstrated by mobility shift assays and methylation interference analysis. Binding and transactivation studies with mutant NRRE-1 elements confirmed the existence of distinct retinoid, COUP-TF, and HNF-4 response elements that define novel receptor binding motifs: COUP-TF homodimers bound sites 1 and 3 (two hexamer repeat sequences arranged as an everted imperfect repeat separated by 14 bp or ER14), RAR-RXR heterodimers bound sites 1 and 2 (ER8), and HNF-4 homodimers bound sites 2 and 3 (imperfect DR0). Mixing cotransfection experiments demonstrated that the nuclear receptor dimers compete at NRRE-1 to modulate constitutive and ligand-mediated transcriptional activity. These data suggest a mechanism for the transcriptional modulation of genes encoding enzymes involved in cellular metabolism.

scholarly journals The Orphan Nuclear Receptor RORα Restrains Adipocyte Differentiation through a Reduction of C/EBPβ Activity and Perilipin Gene Expression

2009 ◽  
Vol 23 (6) ◽  
pp. 759-771 ◽  
Author(s):  
Nobumichi Ohoka ◽  
Shogo Kato ◽  
Yu Takahashi ◽  
Hidetoshi Hayashi ◽  
Ryuichiro Sato
Keyword(s):  
Gene Expression ◽  
Nuclear Receptor ◽  
Adipocyte Differentiation ◽  
Orphan Nuclear Receptor
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