The Experts below are selected from a list of 6477 Experts worldwide ranked by ideXlab platform
Huengsik Choi - One of the best experts on this subject based on the ideXlab platform.
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Orphan Nuclear Receptor ERRγ Is a Transcriptional Regulator of CB1 Receptor-Mediated TFR2 Gene Expression in Hepatocytes
'MDPI AG', 2021Co-Authors: Bo-eun Kim, Huengsik Choi, Byungyoon Choi, Woo-ram Park, Yu-ji Kim, In-young Kim, Yoon Seok Jung, Yong-hoon Kim, Chul-ho Lee, Don-kyu KimAbstract: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
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Orphan Nuclear Receptor estrogen related Receptor γ errγ is key regulator of hepatic gluconeogenesis
Journal of Biological Chemistry, 2012Co-Authors: Seung Bum Park, Huengsik ChoiAbstract:Glucose homeostasis is tightly controlled by hormonal regulation of hepatic glucose production. Dysregulation of this system is often associated with insulin resistance and diabetes, resulting in hyperglycemia in mammals. Here, we show that the Orphan Nuclear Receptor estrogen-related Receptor γ (ERRγ) is a novel downstream mediator of glucagon action in hepatic gluconeogenesis and demonstrate a beneficial impact of the inverse agonist GSK5182. Hepatic ERRγ expression was increased by fasting-dependent activation of the cAMP-response element-binding protein-CRTC2 pathway. Overexpression of ERRγ induced Pck1 and G6PC gene expression and glucose production in primary hepatocytes, whereas abolition of ERRγ gene expression attenuated forskolin-mediated induction of gluconeogenic gene expression. Deletion and mutation analyses of the Pck1 promoter showed that ERRγ directly regulates the Pck1 gene transcription via ERR response elements of the Pck1 promoter as confirmed by ChIP assay and in vivo imaging analysis. We also demonstrate that GSK5182, an inverse agonist of ERRγ, specifically inhibits the transcriptional activity of ERRγ in a PGC-1α dependent manner. Finally, the ERRγ inverse agonist ameliorated hyperglycemia through inhibition of hepatic gluconeogenesis in db/db mice. Control of hepatic glucose production by an ERRγ-specific inverse agonist is a new potential therapeutic approach for the treatment of type 2 diabetes.
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ampk dependent repression of hepatic gluconeogenesis via disruption of creb crtc2 complex by Orphan Nuclear Receptor small heterodimer partner
Journal of Biological Chemistry, 2010Co-Authors: Kwang-hoon Song, Dipanjan Chanda, John Y L Chiang, Huengsik ChoiAbstract:Orphan Nuclear Receptor small heterodimer partner (SHP) plays a key role in transcriptional repression of gluconeogenic enzyme gene expression. Here, we show that SHP inhibited protein kinase A-mediated transcriptional activity of cAMP-response element-binding protein (CREB), a major regulator of glucose metabolism, to modulate hepatic gluconeogenic gene expression. Deletion analysis of phosphoenolpyruvate carboxykinase (PEPCK) promoter demonstrated that SHP inhibited forskolin-mediated induction of PEPCK gene transcription via inhibition of CREB transcriptional activity. In vivo imaging demonstrated that SHP inhibited CREB-regulated transcription coactivator 2 (CRTC2)-mediated cAMP-response element-driven promoter activity. Furthermore, overexpression of SHP using adenovirus SHP decreased CRTC2-dependent elevations in blood glucose levels and PEPCK or glucose-6-phosphatase (G6Pase) expression in mice. SHP and CREB physically interacted and were co-localized in vivo. Importantly, SHP inhibited both wild type CRTC2 and S171A (constitutively active form of CRTC2) coactivator activity and disrupted CRTC2 recruitment on the PEPCK gene promoter. In addition, metformin or overexpression of a constitutively active form of AMPK (Ad-CA-AMPK) inhibited S171A-mediated PEPCK and G6Pase gene expression, and hepatic glucose production and knockdown of SHP partially relieved the metformin- and Ad-CA-AMPK-mediated repression of hepatic gluconeogenic enzyme gene expression in primary rat hepatocytes. In conclusion, our results suggest that a delayed effect of metformin-mediated induction of SHP gene expression inhibits CREB-dependent hepatic gluconeogenesis.
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bile acids inhibit duodenal secretin expression via Orphan Nuclear Receptor small heterodimer partner shp
American Journal of Physiology-gastrointestinal and Liver Physiology, 2009Co-Authors: Ian P Y Lam, Huengsik Choi, Leo T O Lee, Gianfranco Alpini, Billy K C ChowAbstract:Small heterodimer partner (SHP) is an Orphan Nuclear Receptor in which gene expression can be upregulated by bile acids. It regulates its target genes by repressing the transcriptional activities of other Nuclear Receptors including NeuroD, which has been shown to regulate secretin gene expression. Here, we evaluated the regulation on duodenal secretin gene expression by SHP and selected bile acids, cholic acid (CA) and chenodeoxycholic acid (CDCA). In vitro treatment of CDCA or fexaramine elevated the SHP transcript level and occupancy on secretin promoter. The increase in the SHP level, induced by bile acid treatment or overexpression, reduced secretin gene expression, whereas this gene inhibitory effect was reversed by silencing of endogenous SHP. In in vivo studies, double-immunofluorescence staining demonstrated the coexpression of secretin and SHP in mouse duodenum. Feeding mice with 1% CA-enriched rodent chow resulted in upregulation of SHP and a concomitant decrease in secretin transcript and protein levels in duodenum compared with the control group fed with normal chow. A diet enriched with 5% cholestyramine led to a decrease in SHP level and a corresponding increase in secretin expression. Overall, this study showed that bile acids via SHP inhibit duodenal secretin gene expression. Because secretin is a key hormone that stimulates bile flow in cholangiocytes, this pathway thus provides a novel means to modulate secretin-stimulated choleresis in response to intraduodenal bile acids.
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glucotoxicity in the ins 1 rat insulinoma cell line is mediated by the Orphan Nuclear Receptor small heterodimer partner
Diabetes, 2007Co-Authors: Keungyu Park, Joongyeol Park, Li Wang, Huengsik ChoiAbstract:Prolonged elevations of glucose concentration have deleterious effects on β-cell function. One of the hallmarks of such glucotoxicity is a reduction in insulin gene expression, resulting from decreased insulin promoter activity. Small heterodimer partner (SHP; NR0B2) is an atypical Orphan Nuclear Receptor that inhibits Nuclear Receptor signaling in diverse metabolic pathways. In this study, we found that sustained culture of INS-1 cells at high glucose concentrations leads to an increase in SHP mRNA expression, followed by a decrease in insulin gene expression. Inhibition of endogenous SHP gene expression by small interfering RNA partially restored high-glucose–induced suppression of the insulin gene. Adenovirus-mediated overexpression of SHP in INS-1 cells impaired glucose-stimulated insulin secretion as well as insulin gene expression. SHP downregulates insulin gene expression via two mechanisms: by downregulating PDX-1 and MafA gene expression and by inhibiting p300-mediated pancreatic duodenal homeobox factor 1–and BETA2-dependent transcriptional activity from the insulin promoter. Finally, the pancreatic islets of diabetic OLETF rats express SHP mRNA at higher levels than the islets from LETO rats. These results collectively suggest that SHP plays an important role in the development of β-cell dysfunction induced by glucotoxicity.
Mitchell A Lazar - One of the best experts on this subject based on the ideXlab platform.
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the Orphan Nuclear Receptor rev erbα regulates circadian expression of plasminogen activator inhibitor type 1
Journal of Biological Chemistry, 2006Co-Authors: Jing Wang, Lei Yin, Mitchell A LazarAbstract:Abstract Plasminogen activator inhibitor type 1 (PAI-1) is a major physiologic regulator of the fibrinolytic system and has recently gained recognition as a modulator of inflammation and atherosclerosis. PAI-1 exhibits circadian rhythmicity in its expression, peaking in the early morning, which is associated with increased risk for cardiovascular events. However, the mechanisms that determine PAI-1 circadian rhythmicity remain poorly understood. We discovered that the Orphan Nuclear Receptor Reverbα, a core component of the circadian loop, represses human PAI-1 gene expression through two Rev-erbα binding sites in the PAI-1 promoter. Mutations of these sites, as well as RNA interference targeting endogenous Rev-erbα and its corepressors, led to increased expression of the PAI-1 gene. Furthermore, glycogen synthase kinase 3β (GSK3β) contributes to pai-1 repression by phosphorylating and stabilizing Rev-erbα protein, which can be blocked by lithium. Interestingly, serum shock generated circadian oscillations in PAI-1 mRNA in NIH3T3 cells, suggesting that PAI-1 is a direct output gene of the circadian loop. Ectopic expression of a stabilized form of Rev-erbα that mimics GSK3β phosphorylation dramatically dampened PAI-1 circadian oscillations. Thus, our results suggest that Rev-erbα is a major determinant of the circadian PAI-1 expression and a potential modulator of the morning susceptibility to myocardial infarction.
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the Orphan Nuclear Receptor rev erbα recruits the n cor histone deacetylase 3 corepressor to regulate the circadian bmal1 gene
Molecular Endocrinology, 2005Co-Authors: Mitchell A LazarAbstract:Transcriptional regulation plays a fundamental role in controlling circadian oscillation of clock gene expression. The Orphan Nuclear Receptor Rev-erbα has recently been implicated as a major regulator of the circadian clock. Expression of Bmal1, the master regulator of circadian rhythm in mammals, is negatively correlated with Rev-erbα mRNA level, but the molecular mechanism underlying this regulation is largely unknown. Here we show that Rev-erbα dramatically represses the basal activity of the mouse Bmal1 gene promoter via two monomeric binding sites, both of which are required for repression and are conserved between mouse and human. Rev-erbα directly binds to the mouse Bmal1 promoter and recruits the endogenous Nuclear Receptor corepressor (N-CoR)/histone deacetylase 3 (HDAC3) complex, in association with a decrease in histone acetylation. The endogenous N-CoR/HDAC3 complex is also associated with the endogenous Bmal1 promoter in human HepG2 liver cells, where a reduction in cellular HDAC3 level mark...
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the Orphan Nuclear Receptor rev erbα recruits the n cor histone deacetylase 3 corepressor to regulate the circadian bmal1 gene
Molecular Endocrinology, 2005Co-Authors: Lei Yin, Mitchell A LazarAbstract:Transcriptional regulation plays a fundamental role in controlling circadian oscillation of clock gene expression. The Orphan Nuclear Receptor Rev-erbalpha has recently been implicated as a major regulator of the circadian clock. Expression of Bmal1, the master regulator of circadian rhythm in mammals, is negatively correlated with Rev-erbalpha mRNA level, but the molecular mechanism underlying this regulation is largely unknown. Here we show that Rev-erbalpha dramatically represses the basal activity of the mouse Bmal1 gene promoter via two monomeric binding sites, both of which are required for repression and are conserved between mouse and human. Rev-erbalpha directly binds to the mouse Bmal1 promoter and recruits the endogenous Nuclear Receptor corepressor (N-CoR)/histone deacetylase 3 (HDAC3) complex, in association with a decrease in histone acetylation. The endogenous N-CoR/HDAC3 complex is also associated with the endogenous Bmal1 promoter in human HepG2 liver cells, where a reduction in cellular HDAC3 level markedly increases the expression of Bmal1 mRNA. These data demonstrate a new function for the N-CoR/HDAC3 complex in regulating the expression of genes involved in circadian rhythm by functioning as corepressor for Rev-erbalpha.
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transcriptional activation and repression by rorα an Orphan Nuclear Receptor required for cerebellar development
Molecular Endocrinology, 1997Co-Authors: Heather P Harding, Brandon G Atkins, Aron B Jaffe, Mitchell A LazarAbstract:Mutation of the Orphan Nuclear Receptor RORα results in a severe impairment of cerebellar development by unknown mechanisms. We have found that RORα activates transcription from only a subset of sites to which it binds strongly as a monomer. RORα also selectively binds as a homodimer to a direct repeat of this monomer site with a 2-bp spacing between the AGGTCA sequences (Rev-DR2 site) and is a much more potent transcriptional activator on this site than on monomer sites or other direct repeats. To better understand the transcriptional regulatory functions of RORα, we fused its C terminus to a heterologous DNA-binding domain. Mutational analysis revealed that RORα contains both transcriptional activation and transcriptional repression domains, with the repression domain being more active in some cell types. The abilities of RORα polypeptides to repress transcription correlate with their abilities to interact with the Nuclear Receptor corepressors N-CoR and SMRT in vitro. However, the AF2 region of RORα in...
Huiyan Zeng - One of the best experts on this subject based on the ideXlab platform.
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Orphan Nuclear Receptor tr3 nur77 biologics inhibit tumor growth by targeting angiogenesis and tumor cells
Microvascular Research, 2020Co-Authors: Chen Chen, Liuliang Qin, Pierre M Bourbon, Dezheng Zhao, Shiqiang Hou, Kevin Zhao, Huiyan ZengAbstract:Pathological angiogenesis is a hallmark of many diseases. Previously, we reported that Orphan Nuclear Receptor TR3/Nur77 was a critical mediator of angiogenesis to regulate tumor growth, sepsis and skin wound healing. However, none of the TR3/Nur77 targeting molecule has been in clinical trial so far. Here, we designed and generated novel TR3 shRNAs and two minigenes that had therapeutic potential for cancer treatment. In addition to extend our previous findings that tumor growth was inhibited in Nur77 knockout mice, we found that metastasis of colorectal tumor was completely inhibited in Nur77-/- mice. Tumor masses were increased ~70% and decreased ~40% in our transgenic EC-Nur77-S mice and EC-Nur77-DN mice, in which the full-length cDNA and the dominant negative mutant of TR3/Nur77 were inducibly and specifically expressed in mouse endothelium, respectively. TR3 was highly expressed in the vasculature and tumor cells of human melanoma and colorectal cancer tissues, but not in normal tissues. The novel TR3 shRNAs and two minigenes almost completely inhibited the proliferation and migration of HUVECs and human melanoma A375sm cells. Angiogenesis induced by adenoviruses expressing VEGF and melanoma growth in mice were greatly and significantly inhibited by systemically administration of adenoviruses expressing TR3 shRNAs and two minigenes. Tumor angiogenesis and the expressions of genes associated with angiogenesis were greatly regulated in tumor tissues treated with TR3 shRNAs and minigenes. Taken together, these studies demonstrated that TR3/Nur77 was a specific therapeutic target for several human cancers by targeting both tumor cells and tumor microenvironment. These TR3/Nur77 biologics inhibit angiogenesis and tumor growth, and have translational potential.
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dll4 and jagged1 are angiogenic targets of Orphan Nuclear Receptor tr3 nur77
Microvascular Research, 2019Co-Authors: Jin Peng, Gengming Niu, Shengqiang Zhao, Dezheng Zhao, Chen Chen, Huiyan ZengAbstract:Pathological angiogenesis is a hallmark of many diseases. Previously, we reported that Orphan Nuclear Receptor TR3/Nur77 was a critical mediator of angiogenesis to regulate tumor growth and skin wound healing via regulating the expression of the junctional proteins and integrins. However, the molecular mechanism, by which TR3/Nur77 regulates angiogenesis is not completely understood. Here, we were the first to find that TR3/Nur77, via its various amino acid fragments, regulated the expression of DLL4 and Jagged 1 in cultured endothelial cells. DLL4 and Jagged1 mediated TR3/Nur77-induced angiogenic responses and signaling molecules, but not the expression of integrins. Instead, integrins regulated the expressions of DLL4 and Jagged1 induced by TR3/Nur77. Further, DLL4, Jagged1 and integrins α1, α2, β3 and β5 were regulated by TR3/Nur77 in animal sepsis models of lipopolysaccharide (LPS)-induced endotoxemia, and cecal ligation and puncture (CLP), in which, TR3/Nur77 expression was significantly and tranciently increased. Mouse survival rates were greatly increased in Nur77 knockout mice bearing both CLP and LPS models. The results elucidated a novel axis of VEGF/histamine ➔ TR3/Nur77 ➔ integrins ➔ DLL4/Jagged1 in angiogenesis, and demonstrated that TR3/Nur77 was an excellent target for sepsis. These studies supported our previous findings that TR3/Nur77 was an excellent therapeutic target, and further our understanding of the molecular mechanism, by which TR3/Nur77 regulated angiogenesis.
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Orphan Nuclear Receptor tr3 nur77 differentially regulates the expression of integrins in angiogenesis
Microvascular Research, 2019Co-Authors: Gengming Niu, Huiyan Zeng, Jin Peng, Xin Liu, Shiqiang Hou, Dezheng ZhaoAbstract:Abstract Pathological angiogenesis is a hallmark of many diseases. Previously, we reported that Orphan Nuclear Receptor TR3/Nur77 (human homolog, Nur77, mouse homolog) is a critical mediator of angiogenesis to regulate tumor growth and skin wound healing via down-regulating the expression of the junctional proteins and integrin β4. However, the molecular mechanism, by which TR3/Nur77 regulated angiogenesis, was still not completely understood. In this report by analyzing the integrin expression profile in endothelial cells, we found that the TR3/Nur77 expression highly increased the expression of integrins α1 and β5, decreased the expression of integrins α2 and β3, but had some or no effect on the expression of integrins αv, α3, α4, α5, α6, β1 and β7. In the angiogenic responses mediated by TR3/Nur77, integrin α1 regulated endothelial cell proliferation and adhesion, but not migration. Integrin β5 shRNA inhibited cell migration, but increased proliferation and adhesion. Integrin α2 regulated all of the endothelial cell proliferation, migration and adhesion. However, integrin β3 did not play any role in endothelial cell proliferation, migration and adhesion. TR3/Nur77 regulated the transcription of integrins α1, α2, β3 and β5, via various amino acid fragments within its transactivation domain and DNA binding domain. Furthermore, TR3/Nur77 regulated the integrin α1 promoter activity by directly interacting with a novel DNA element within the integrin α1 promoter. These studies furthered our understanding of the molecular mechanism by which TR3/Nur77 regulated angiogenesis, and supported our previous finding that TR3/Nur77 was an excellent therapeutic target for pathological angiogenesis. Therefore, targeting TR3/Nur77 inhibits several signaling pathways that are activated by various angiogenic factors.
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expressions of Orphan Nuclear Receptor tr3 nur77 in chronic hepatopathy and its clinical significance
Journal of Clinical & Experimental Oncology, 2017Co-Authors: Yingling Zeng, Dezheng Zhao, Degui Liao, Shizhang Huang, Huinan Mao, Huiyan ZengAbstract:Objective: Although great success has been achieved in cancer treatment, current cancer therapies, including anti-tumorigenesis and anti-angiogenesis, still face the problems of insufficient efficacy, resistance and intrinsic refractoriness, in addition to their toxic side effects. There is a demand to identify additional targets that can be blocked to turn off the downstream effects of most, if not all, pathways. Our studies suggest that Orphan Nuclear Receptor TR3 (human) / Nur77 (mouse) is such a target. Most recently, we reported that TR3/Nur77 expression in human hepatic cancer tissues correlates well with tumor progress, suggesting that TR3 is a specific therapeutic target for hepatic cancers. However, the correlation of TR3/Nur77 expression in hepatocellular carcinoma (HCC) with chronic hepatitis has not been studied. Methods: The expression of TR3/Nur77 was analysed in human primary hepatic cancer specimens from patients that have complete medical records with Immunohistochemically staining. The statistical analysis was used to access the significance of TR3 expression in tumor tissues, cirrhosis tissues and chronic hepatitis tissues with and without hepatitis B virus infection (HBV (+) and HBV (-)), which were obtained from para-tumor tissues. Results: The positive rates of TR3 / Nur77 expression in hepatocellular carcinoma, cancerous liver cirrhosis and chronic hepatitis are 66.67%, 30%, and 20%, respectively, which are statistic significant (p
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Orphan Nuclear Receptor tr3 nur77 is a specific therapeutic target for hepatic cancers
Journal of Clinical & Experimental Oncology, 2017Co-Authors: Yingling Zeng, Dezheng Zhao, Degui Liao, Shizhang Huang, Huinan Mao, Huiyan ZengAbstract:Objective: Although great success has been achieved in cancer treatment, current cancer therapies, including anti-tumorigenesis and anti-angiogenesis, still face the problems of insufficient efficacy, resistance and intrinsic refractoriness, in addition to their toxic side effects. There is a demand to identify additional targets that can be blocked to turn off the downstream effects of most, if not all, pathways. Our previous studies suggest that Orphan Nuclear Receptor TR3 (human) / Nur77 (mouse) is such a target. However, the correlation of TR3 expression and clinical tumor progression has not been studied. Methods: The expression of TR3 was analysed in human primary hepatic cancer specimens from patients that have complete medical records with Immunohistochemical staining. The statistical analysis was used to assess the significance of TR3 expression in tumor tissues, paratumor tissues and normal tissues, and to investigate the correlation of TR3 expression and clincopathologic characteristics. Results: TR3 is highly expressed in human hepatic cancer tissues, but not in normal liver tissues. The positive expression yields of TR3 are 67.67% (14/21), 19.05% (4/21) and 0% (0/10) in cancer tissues, para cancer tissues, and normal liver tissue, respectively, which are statistic significant (χ2=17.07, p<0.005). The expression of TR3 is significantly higher in cancer tissues than in para cancer tissues (χ2=9.722, p<0.005) and in normal tissues (p< 0.0005). The levels of TR3 expression in human hepatic cancer tissues correlates well with tumors that are at low/middle degree of tumor differentiation and have portal vein thrombosis, metastasis and recurrence, but not with age, gender, tumor number and Alpha-fetal protein (AFP) volume. Conclusion: The results indicate that TR3 is a specific therapeutic target for hepatic cancers.
Li Wang - One of the best experts on this subject based on the ideXlab platform.
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Modulation of Orphan Nuclear Receptor Nur77-Mediated Apoptotic Pathway by Acetylshikonin and Analogues
Cancer research, 2008Co-Authors: Jie Liu, Bingzhen Lin, Xihua Cao, Zhe Sun, Wen Zhou, Yuan-yuan Lang, Tingdong Yan, Li WangAbstract:Shikonin derivatives, which are the active components of the medicinal plant Lithospermum erythrorhizon, exhibit many biological effects including apoptosis induction through undefined mechanisms. We recently discovered that Orphan Nuclear Receptor Nur77 migrates from the nucleus to the mitochondria, where it binds to Bcl-2 to induce apoptosis. Here, we report that certain shikonin derivatives could modulate the Nur77/Bcl-2 apoptotic pathway by increasing levels of Nur77 protein and promoting its mitochondrial targeting in cancer cells. Structural modification of acetylshikonin resulted in the identification of a derivative 5,8-diacetoxyl-6-(1'-acetoxyl-4'-methyl-3'-pentenyl)-1,4-naphthaquinones (SK07) that exhibited improved efficacy and specificity in activating the pathway. Unlike other Nur77 modulators, shikonins increased the levels of Nur77 protein through their posttranscriptional regulation. The apoptotic effect of SK07 was impaired in Nur77 knockout cells and suppressed by cotreatment with leptomycin B that inhibited Nur77 cytoplasmic localization. Furthermore, SK07 induced apoptosis in cells expressing the COOH-terminal half of Nur77 protein but not its NH(2)-terminal region. Our data also showed that SK07-induced apoptosis was associated with a Bcl-2 conformational change and Bax activation. Together, our results show that certain shikonin derivatives act as modulators of the Nur77-mediated apoptotic pathway and identify a new shikonin-based lead that targets Nur77 for apoptosis induction.
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glucotoxicity in the ins 1 rat insulinoma cell line is mediated by the Orphan Nuclear Receptor small heterodimer partner
Diabetes, 2007Co-Authors: Keungyu Park, Joongyeol Park, Li Wang, Huengsik ChoiAbstract:Prolonged elevations of glucose concentration have deleterious effects on β-cell function. One of the hallmarks of such glucotoxicity is a reduction in insulin gene expression, resulting from decreased insulin promoter activity. Small heterodimer partner (SHP; NR0B2) is an atypical Orphan Nuclear Receptor that inhibits Nuclear Receptor signaling in diverse metabolic pathways. In this study, we found that sustained culture of INS-1 cells at high glucose concentrations leads to an increase in SHP mRNA expression, followed by a decrease in insulin gene expression. Inhibition of endogenous SHP gene expression by small interfering RNA partially restored high-glucose–induced suppression of the insulin gene. Adenovirus-mediated overexpression of SHP in INS-1 cells impaired glucose-stimulated insulin secretion as well as insulin gene expression. SHP downregulates insulin gene expression via two mechanisms: by downregulating PDX-1 and MafA gene expression and by inhibiting p300-mediated pancreatic duodenal homeobox factor 1–and BETA2-dependent transcriptional activity from the insulin promoter. Finally, the pancreatic islets of diabetic OLETF rats express SHP mRNA at higher levels than the islets from LETO rats. These results collectively suggest that SHP plays an important role in the development of β-cell dysfunction induced by glucotoxicity.
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the Orphan Nuclear Receptor shp regulates pgc 1α expression and energy production in brown adipocytes
Cell Metabolism, 2005Co-Authors: Li Wang, Jun Liu, Pradip K. Saha, Jiansheng Huang, Lawrence Chan, Bruce M Spiegelman, David D MooreAbstract:Brown adipocytes increase energy production in response to induction of PGC-1alpha, a dominant regulator of energy metabolism. We have found that the Orphan Nuclear Receptor SHP (NR0B2) is a negative regulator of PGC-1alpha expression in brown adipocytes. Mice lacking SHP show increased basal expression of PGC-1alpha, increased energy expenditure, and resistance to diet-induced obesity. Increased PGC-1alpha expression in SHP null brown adipose tissue is not due to beta-adrenergic activation, since it is also observed in primary cultures of SHP(-/-) brown adipocytes that are not exposed to such stimuli. In addition, acute inhibition of SHP expression in cultured wild-type brown adipocytes increases basal PGC-1alpha expression, and SHP overexpression in SHP null brown adipocytes decreases it. The Orphan Nuclear Receptor ERRgamma is expressed in BAT and its transactivation of the PGC-1alpha promoter is potently inhibited by SHP. We conclude that SHP functions as a negative regulator of energy production in BAT.
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The Orphan Nuclear Receptor SHP regulates PGC-1α expression and energy production in brown adipocytes
Cell metabolism, 2005Co-Authors: Li Wang, Jun Liu, Pradip K. Saha, Jiansheng Huang, Lawrence Chan, Bruce Spiegelman, David D MooreAbstract:Summary Brown adipocytes increase energy production in response to induction of PGC-1α, a dominant regulator of energy metabolism. We have found that the Orphan Nuclear Receptor SHP (NR0B2) is a negative regulator of PGC-1α expression in brown adipocytes. Mice lacking SHP show increased basal expression of PGC-1α, increased energy expenditure, and resistance to diet-induced obesity. Increased PGC-1α expression in SHP null brown adipose tissue is not due to β-adrenergic activation, since it is also observed in primary cultures of SHP −/− brown adipocytes that are not exposed to such stimuli. In addition, acute inhibition of SHP expression in cultured wild-type brown adipocytes increases basal PGC-1α expression, and SHP overexpression in SHP null brown adipocytes decreases it. The Orphan Nuclear Receptor ERRγ is expressed in BAT and its transactivation of the PGC-1α promoter is potently inhibited by SHP. We conclude that SHP functions as a negative regulator of energy production in BAT.
David D Moore - One of the best experts on this subject based on the ideXlab platform.
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the Orphan Nuclear Receptor shp regulates pgc 1α expression and energy production in brown adipocytes
Cell Metabolism, 2005Co-Authors: Li Wang, Jun Liu, Pradip K. Saha, Jiansheng Huang, Lawrence Chan, Bruce M Spiegelman, David D MooreAbstract:Brown adipocytes increase energy production in response to induction of PGC-1alpha, a dominant regulator of energy metabolism. We have found that the Orphan Nuclear Receptor SHP (NR0B2) is a negative regulator of PGC-1alpha expression in brown adipocytes. Mice lacking SHP show increased basal expression of PGC-1alpha, increased energy expenditure, and resistance to diet-induced obesity. Increased PGC-1alpha expression in SHP null brown adipose tissue is not due to beta-adrenergic activation, since it is also observed in primary cultures of SHP(-/-) brown adipocytes that are not exposed to such stimuli. In addition, acute inhibition of SHP expression in cultured wild-type brown adipocytes increases basal PGC-1alpha expression, and SHP overexpression in SHP null brown adipocytes decreases it. The Orphan Nuclear Receptor ERRgamma is expressed in BAT and its transactivation of the PGC-1alpha promoter is potently inhibited by SHP. We conclude that SHP functions as a negative regulator of energy production in BAT.
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The Orphan Nuclear Receptor SHP regulates PGC-1α expression and energy production in brown adipocytes
Cell metabolism, 2005Co-Authors: Li Wang, Jun Liu, Pradip K. Saha, Jiansheng Huang, Lawrence Chan, Bruce Spiegelman, David D MooreAbstract:Summary Brown adipocytes increase energy production in response to induction of PGC-1α, a dominant regulator of energy metabolism. We have found that the Orphan Nuclear Receptor SHP (NR0B2) is a negative regulator of PGC-1α expression in brown adipocytes. Mice lacking SHP show increased basal expression of PGC-1α, increased energy expenditure, and resistance to diet-induced obesity. Increased PGC-1α expression in SHP null brown adipose tissue is not due to β-adrenergic activation, since it is also observed in primary cultures of SHP −/− brown adipocytes that are not exposed to such stimuli. In addition, acute inhibition of SHP expression in cultured wild-type brown adipocytes increases basal PGC-1α expression, and SHP overexpression in SHP null brown adipocytes decreases it. The Orphan Nuclear Receptor ERRγ is expressed in BAT and its transactivation of the PGC-1α promoter is potently inhibited by SHP. We conclude that SHP functions as a negative regulator of energy production in BAT.
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differential regulation of the Orphan Nuclear Receptor small heterodimer partner shp gene promoter by Orphan Nuclear Receptor err isoforms
Journal of Biological Chemistry, 2002Co-Authors: Sabyasachi Sanyal, David D Moore, Joonyoung Kim, Hanjong Kim, Jun Takeda, Yoonkwang Lee, Huengsik ChoiAbstract:The Orphan Nuclear Receptor small heterodimer partner (SHP; NR0B2) interacts with a wide array of Nuclear Receptors and represses their transcriptional activity. SHP expression is regulated by several other members of the Nuclear Receptor superfamily, including the Orphan Receptors SF-1 and LRH-1, and the bile acid Receptor FXR. We have found that the SHP promoter is also activated by the estrogen Receptor-related Receptor γ (ERRγ) but not the related ERRα and ERRβ isoforms. SHP and ERRγ mRNAs are coexpressed in several tissues, including pancreas, kidney, and heart, confirming the potential relevance of this transactivation. ERRγ transactivation is dependent on only one of five previously characterized DNA-binding sites for SF-1, and this element differs from previously reported ERR response elements. However, treatment with the histone deacetylase inhibitor trichostatin A significantly increased ERRα and ERRβ activity on this element indicating that the lack of activity of ERRα and -β may depend on their association with co-repressor in vivo. Furthermore, using protease sensitivity assays on DNA bound Receptors it was demonstrated that DNA sequence of different response elements may cause allosteric modulation of ERR proteins, which in turn may be responsible for the differential activities of these Receptors on different response elements. SHP inhibits ERRγ transactivation and physically interacts with all three members of ERR subfamily, as demonstrated by both yeast two-hybrid and biochemical assays. As with other SHP targets, this interaction is dependent on the AF-2 coactivator-binding site of ERRγ and the previously described N-terminal Receptor interaction domain of SHP. Several recently described SHP mutations associated with moderate obesity in humans block the inhibition of ERRγ activity. Overall, these results identify a new autoregulatory loop controlling SHP gene expression and significantly extend the potential functional roles of the three ERRs.
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bile acids natural ligands for an Orphan Nuclear Receptor
Science, 1999Co-Authors: Derek J Parks, Steven A Kliewer, Steven G Blanchard, Randy K Bledsoe, Gyan Chandra, Thomas G Consler, Julie B Stimmel, Timothy M Willson, Ann Marie Zavacki, David D MooreAbstract:Bile acids regulate the transcription of genes that control cholesterol homeostasis through molecular mechanisms that are poorly understood. Physiological concentrations of free and conjugated chenodeoxycholic acid, lithocholic acid, and deoxycholic acid activated the farnesoid X Receptor (FXR; NR1H4), an Orphan Nuclear Receptor. As ligands, these bile acids and their conjugates modulated interaction of FXR with a peptide derived from steroid Receptor coactivator 1. These results provide evidence for a Nuclear bile acid signaling pathway that may regulate cholesterol homeostasis.