scholarly journals Oxysterol Nuclear Receptor LXRβ Regulates Cholesterol Homeostasis and Contractile Function in Mouse Uterus

2006 ◽  
Vol 282 (7) ◽  
pp. 4693-4701 ◽  
Author(s):  
Kevin Mouzat ◽  
Magali Prod'Homme ◽  
David H. Volle ◽  
Benoit Sion ◽  
Pierre Déchelotte ◽  
...  
Keyword(s):  
Cholesteryl Ester ◽  
Nuclear Receptor ◽  
Target Genes ◽  
Contractile Function ◽  
Contractile Activity ◽  
Critical Role ◽  
Cholesterol Homeostasis ◽  
Protective Mechanism ◽  
Mouse Uterus ◽  
Expression Of Genes

The uterus is an organ where lipid distribution plays a critical role for its function. Here we show that nuclear receptor for oxysterols LXRβ prevents accumulation of cholesteryl esters in mouse myometrium by controlling expression of genes involved in cholesterol efflux and storage (abca1 and abcg1). Upon treatment with an LXR agonist that mimics activation by oxysterols, expression of these target genes was increased in wild-type mice, whereas under basal conditions, lxrα;β-/- mice exhibited a marked decrease in abcg1 accumulation. This change resulted in a phenotype of cholesteryl ester accumulation. Besides, a defect of contractile activity induced by oxytocin or PGF2α was observed in mice lacking LXRβ. These results imply that LXRβ provides a safety valve to limit cholesteryl ester levels as a basal protective mechanism in the uterus against cholesterol accumulation and is necessary for a correct induction of contractions.

Abstract 403: Identification of CHROME as a Competing Endogenous RNA that Regulates Cholesterol Homeostasis

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Coen van Solingen ◽  
Elizabeth J Hennessy ◽  
Mireille Ouimet ◽  
Kaitlyn Rinehold ◽  
Maryem Hussein ◽  
...  
Keyword(s):  
Cholesterol Efflux ◽  
Target Genes ◽  
Hdl Cholesterol ◽  
Cholesterol Homeostasis ◽  
Competing Endogenous Rna ◽  
Cellular Cholesterol ◽  
Expression Of Genes ◽  
Non Coding Rna ◽  
Non Coding Rnas ◽  
X Receptors

The discovery of microRNAs (miRNA) targeting gene pathways involved in HDL and LDL metabolism illuminated the potent role of non-coding RNAs in the regulation of cholesterol homeostasis. Long non-coding RNAs (lncRNA) have also been identified as crucial regulators of gene expression; however, few have been fully characterized. Here we report a novel human lncRNA, CHROME (Cholesterol Homeostasis Regulator Of MicroRNA Expression), that functions as a competing endogenous RNA to regulate cellular cholesterol homeostasis. We show that CHROME has 7 broadly expressed variants that are transcriptionally regulated by the cholesterol-sensing liver X receptors. Computational analyses revealed that CHROME harbors binding sites for multiple (11) miRNAs involved in cholesterol homeostasis, including miR-27b and miR-33a/b, which function as hubs controlling the expression of genes involved in cholesterol efflux and HDL metabolism. Using CHROME knock-down and overexpression, we demonstrate that CHROME acts as a ‘miRNA sponge’ that sequesters these miRNAs, limiting their ability to repress target genes, including ABCA1, OSBPL6 and ANGPTL3. Consistent with this, we show that overexpression of CHROME increases cholesterol efflux, whereas its silencing reduces cholesterol efflux from primary human hepatocytes and macrophages. As hepatic cholesterol efflux via ABCA1 plays a central role in HDL biogenesis, we investigated the relationship of CHROME to its miRNA targets and plasma levels of HDL cholesterol in liver samples from a cohort of 200 healthy individuals. This analysis showed that CHROME is inversely correlated with miR-27b and miR-33a/b levels, and positively correlated with levels of their target genes and plasma HDL cholesterol. Collectively, these findings identify CHROME as a key regulatory component of the non-coding RNA circuitry that controls cellular cholesterol efflux and plasma HDL levels in humans.

scholarly journals Liver X Receptors Interact with Corepressors to Regulate Gene Expression

2003 ◽  
Vol 17 (6) ◽  
pp. 1019-1026 ◽  
Author(s):  
Xiao Hu ◽  
Suzhen Li ◽  
Jun Wu ◽  
Chunsheng Xia ◽  
Deepak S. Lala
Keyword(s):  
Gene Expression ◽  
Nuclear Receptor ◽  
Target Gene ◽  
Critical Role ◽  
Cholesterol Homeostasis ◽  
Liver X Receptors ◽  
Regulate Gene Expression ◽  
Target Gene Expression ◽  
X Receptors ◽  
Regulate Gene

Abstract Liver X receptors (LXRs) are members of the nuclear receptor superfamily that regulate gene expression in response to oxysterols and play a critical role in cholesterol homeostasis by regulating genes that are involved in cholesterol transport, catabolism, and triglyceride synthesis. Oxysterols and synthetic agonists bind LXRs and activate transcription by recruiting coactivator proteins. The role of LXRs in regulating target gene expression in the absence of ligand is unknown. Here we show that LXRs interact with corepressors, N-CoR (nuclear receptor corepressor) and SMRT (silent mediator of retinoic acid receptor and thyroid receptor), which are released upon binding agonists. The LXR-corepressor interaction is isoform selective, wherein LXRα has a very strong interaction with corepressors and LXRβ only shows weak interaction. LXRs also exhibit a preference for interacting with N-CoR vs. SMRT. Similar to other nuclear receptors, mutations in the LXR helix 3 and 4 region abolish corepressor interaction. Using a transient transfection assay, we demonstrate that LXR represses transcription that can be further increased by cotransfecting N-CoR into cells. Chromatin immunoprecipitation experiments further indicated that N-CoR is recruited onto endogenous LXR target genes, and addition of LXR agonists releases N-CoR from their promoters. Collectively, these results suggest that corepressors play an important role in regulating LXR target gene expression.

scholarly journals A structural signature motif enlightens the origin and diversification of nuclear receptors

PLoS Genetics ◽  
2021 ◽  
Vol 17 (4) ◽  
pp. e1009492
Author(s):  
Brice Beinsteiner ◽  
Gabriel V. Markov ◽  
Stéphane Erb ◽  
Yassmine Chebaro ◽  
Alastair G. McEwen ◽  
...  
Keyword(s):  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Regulatory Networks ◽  
Evolutionary History ◽  
Target Genes ◽  
Critical Role ◽  
Evolutionary Diversification ◽  
History Of ◽  
Structural Signature ◽  
Α Helix

Nuclear receptors are ligand-activated transcription factors that modulate gene regulatory networks from embryonic development to adult physiology and thus represent major targets for clinical interventions in many diseases. Most nuclear receptors function either as homodimers or as heterodimers. The dimerization is crucial for gene regulation by nuclear receptors, by extending the repertoire of binding sites in the promoters or the enhancers of target genes via combinatorial interactions. Here, we focused our attention on an unusual structural variation of the α-helix, called π-turn that is present in helix H7 of the ligand-binding domain of RXR and HNF4. By tracing back the complex evolutionary history of the π-turn, we demonstrate that it was present ancestrally and then independently lost in several nuclear receptor lineages. Importantly, the evolutionary history of the π-turn motif is parallel to the evolutionary diversification of the nuclear receptor dimerization ability from ancestral homodimers to derived heterodimers. We then carried out structural and biophysical analyses, in particular through point mutation studies of key RXR signature residues and showed that this motif plays a critical role in the network of interactions stabilizing homodimers. We further showed that the π-turn was instrumental in allowing a flexible heterodimeric interface of RXR in order to accommodate multiple interfaces with numerous partners and critical for the emergence of high affinity receptors. Altogether, our work allows to identify a functional role for the π-turn in oligomerization of nuclear receptors and reveals how this motif is linked to the emergence of a critical biological function. We conclude that the π-turn can be viewed as a structural exaptation that has contributed to enlarging the functional repertoire of nuclear receptors.

scholarly journals A Structural Signature Motif Enlightens the Origin and Diversification of Nuclear Receptors

2020 ◽  
Author(s):  
Brice Beinsteiner ◽  
Gabriel V. Markov ◽  
Stéphane Erb ◽  
Yassmine Chebaro ◽  
Alastair McEwen ◽  
...  
Keyword(s):  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Regulatory Networks ◽  
Evolutionary History ◽  
Target Genes ◽  
Critical Role ◽  
Evolutionary Diversification ◽  
History Of ◽  
Structural Signature ◽  
Α Helix

AbstractNuclear receptors are ligand-activated transcription factors that modulate gene regulatory networks from embryonic development to adult physiology and thus represent major targets for clinical interventions in many diseases. Most nuclear receptors function either as homodimers or as heterodimers. The dimerization is crucial for gene regulation by nuclear receptors, by extending the repertoire of binding sites in the promoters or the enhancers of target genes via combinatorial interactions. Here, we focused our attention on an unusual structural variation of the α-helix, called π-turn that is present in helix H7 of the ligand-binding domain of RXR and HNF4. By tracing back the complex evolutionary history of the π-turn, we demonstrate that it was present ancestrally and then independently lost in several nuclear receptor lineages. Importantly, the evolutionary history of the π-turn motif is parallel to the evolutionary diversification of the nuclear receptor dimerization ability from ancestral homodimers to derived heterodimers. We then carried out structural and biophysical analyses, in particular through point mutation studies of key RXR signature residues and showed that this motif plays a critical role in the network of interactions stabilizing homodimers. We further showed that the π-turn was instrumental in allowing a flexible heterodimeric interface of RXR in order to accommodate multiple interfaces with numerous partners and critical for the emergence of high affinity receptors. Altogether, our work allows to identify a functional role for the π-turn in oligomerization of nuclear receptors and reveals how this motif is linked to the emergence of a critical biological function. We conclude that the π-turn can be viewed as a structural exaptation that has contributed to enlarging the functional repertoire of nuclear receptors.

scholarly journals Retinoid X Receptor: Cellular and Biochemical Roles of Nuclear Receptor with a Focus on Neuropathological Involvement

2022 ◽  
Author(s):  
Samridhi Sharma ◽  
Ting Shen ◽  
Nitin Chitranshi ◽  
Veer Gupta ◽  
Devaraj Basavarajappa ◽  
...  
Keyword(s):  
Nuclear Receptor ◽  
Critical Role ◽  
Future Research ◽  
Protective Effects ◽  
Biochemical Processes ◽  
Expression Of Genes ◽  
X Receptors ◽  
Nuclear Receptor Family ◽  
Cumulative Evidence ◽  
Neuronal Stress

AbstractRetinoid X receptors (RXRs) present a subgroup of the nuclear receptor superfamily with particularly high evolutionary conservation of ligand binding domain. The receptor exists in α, β, and γ isotypes that form homo-/heterodimeric complexes with other permissive and non-permissive receptors. While research has identified the biochemical roles of several nuclear receptor family members, the roles of RXRs in various neurological disorders remain relatively under-investigated. RXR acts as ligand-regulated transcription factor, modulating the expression of genes that plays a critical role in mediating several developmental, metabolic, and biochemical processes. Cumulative evidence indicates that abnormal RXR signalling affects neuronal stress and neuroinflammatory networks in several neuropathological conditions. Protective effects of targeting RXRs through pharmacological ligands have been established in various cell and animal models of neuronal injury including Alzheimer disease, Parkinson disease, glaucoma, multiple sclerosis, and stroke. This review summarises the existing knowledge about the roles of RXR, its interacting partners, and ligands in CNS disorders. Future research will determine the importance of structural and functional heterogeneity amongst various RXR isotypes as well as elucidate functional links between RXR homo- or heterodimers and specific physiological conditions to increase drug targeting efficiency in pathological conditions.

scholarly journals Molecular Dynamics of Cobalt Protoporphyrin Antagonism of the Cancer Suppressor REV-ERBβ

Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3251
Author(s):  
Taufik Muhammad Fakih ◽  
Fransiska Kurniawan ◽  
Muhammad Yusuf ◽  
Mudasir Mudasir ◽  
Daryono Hadi Tjahjono
Keyword(s):  
Binding Site ◽  
Nuclear Receptor ◽  
Target Genes ◽  
Protoporphyrin Ix ◽  
Binding Energies ◽  
Metal Center ◽  
Complex Nature ◽  
Dynamic Simulations ◽  
Subtle Change ◽  
Cobalt Protoporphyrin

Nuclear receptor REV-ERBβ is an overexpressed oncoprotein that has been used as a target for cancer treatment. The metal-complex nature of its ligand, iron protoporphyrin IX (Heme), enables the REV-ERBβ to be used for multiple therapeutic modalities as a photonuclease, a photosensitizer, or a fluorescence imaging agent. The replacement of iron with cobalt as the metal center of protoporphyrin IX changes the ligand from an agonist to an antagonist of REV-ERBβ. The mechanism behind that phenomenon is still unclear, despite the availability of crystal structures of REV-ERBβ in complex with Heme and cobalt protoporphyrin IX (CoPP). This study used molecular dynamic simulations to compare the effects of REV-ERBβ binding to Heme and CoPP, respectively. The initial poses of Heme and CoPP in complex with agonist and antagonist forms of REV-ERBβ were predicted using molecular docking. The binding energies of each ligand were calculated using the MM/PBSA method. The computed binding affinity of Heme to REV-ERBβ was stronger than that of CoPP, in agreement with experimental results. CoPP altered the conformation of the ligand-binding site of REV-ERBβ, disrupting the binding site for nuclear receptor corepressor, which is required for REV-ERBβ to regulate the transcription of downstream target genes. Those results suggest that a subtle change in the metal center of porphyrin can change the behavior of porphyrin in cancer cell signaling. Therefore, modification of porphyrin-based agents for cancer therapy should be conducted carefully to avoid triggering unfavorable effects.

scholarly journals Mechanism of protective effect of xuan-bai-cheng-qi decoction on LPS-induced acute lung injury based on an integrated network pharmacology and RNA-sequencing approach

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Huahe Zhu ◽  
Shun Wang ◽  
Cong Shan ◽  
Xiaoqian Li ◽  
Bo Tan ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Rna Sequencing ◽  
Target Genes ◽  
Mammalian Target Of Rapamycin ◽  
Network Pharmacology ◽  
Protective Mechanism ◽  
Rna Seq ◽  
Active Components ◽  
Integrated Network

AbstractXuan-bai-cheng-qi decoction (XCD), a traditional Chinese medicine (TCM) prescription, has been widely used to treat a variety of respiratory diseases in China, especially to seriously infectious diseases such as acute lung injury (ALI). Due to the complexity of the chemical constituent, however, the underlying pharmacological mechanism of action of XCD is still unclear. To explore its protective mechanism on ALI, firstly, a network pharmacology experiment was conducted to construct a component-target network of XCD, which identified 46 active components and 280 predicted target genes. Then, RNA sequencing (RNA-seq) was used to screen differentially expressed genes (DEGs) between ALI model rats treated with and without XCD and 753 DEGs were found. By overlapping the target genes identified using network pharmacology and DEGs using RNA-seq, and subsequent protein–protein interaction (PPI) network analysis, 6 kernel targets such as vascular epidermal growth factor (VEGF), mammalian target of rapamycin (mTOR), AKT1, hypoxia-inducible factor-1α (HIF-1α), and phosphoinositide 3-kinase (PI3K) and gene of phosphate and tension homology deleted on chromsome ten (PTEN) were screened out to be closely relevant to ALI treatment. Verification experiments in the LPS-induced ALI model rats showed that XCD could alleviate lung tissue pathological injury through attenuating proinflammatory cytokines release such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β. Meanwhile, both the mRNA and protein expression levels of PI3K, mTOR, HIF-1α, and VEGF in the lung tissues were down-regulated with XCD treatment. Therefore, the regulations of XCD on PI3K/mTOR/HIF-1α/VEGF signaling pathway was probably a crucial mechanism involved in the protective mechanism of XCD on ALI treatment.

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