Regulation of cytochrome P450 (CYP) genes by nuclear receptors

2000 ◽  
Vol 347 (2) ◽  
pp. 321-337 ◽  
Author(s):  
Paavo HONKAKOSKI ◽  
Masahiko NEGISHI
Keyword(s):  
Cytochrome P450 ◽  
Ligand Binding ◽  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Target Genes ◽  
Physiological Functions ◽  
Nuclear Receptor Superfamily ◽  
Cyp Isoforms ◽  
Exogenous Compounds

Members of the nuclear-receptor superfamily mediate crucial physiological functions by regulating the synthesis of their target genes. Nuclear receptors are usually activated by ligand binding. Cytochrome P450 (CYP) isoforms often catalyse both formation and degradation of these ligands. CYPs also metabolize many exogenous compounds, some of which may act as activators of nuclear receptors and disruptors of endocrine and cellular homoeostasis. This review summarizes recent findings that indicate that major classes of CYP genes are selectively regulated by certain ligand-activated nuclear receptors, thus creating tightly controlled networks.

scholarly journals SUN-LB138 Dynamic Structural Model of Testosterone Entry Into the Unliganded Androgen Receptor

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Irina Krylova ◽  
Fred J Schaufele ◽  
Christophe Guilbert
Keyword(s):  
Amino Acids ◽  
Androgen Receptor ◽  
Ligand Binding ◽  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Binding Pocket ◽  
Binding Domain ◽  
Receptor Ligand ◽  
Ligand Binding Pocket ◽  
Crystallographic Structures

Abstract Background: Crystallographic structures of nuclear receptor ligand binding domains provide a static model of a receptor stably wrapped around an internalized ligand. Understanding the dynamics of a receptor at different stages of ligand binding has been hampered by the paucity of crystal structures for unliganded nuclear receptors. Molecular dynamic models have been constructed for some nuclear receptors to fill that void. Methods: The molecular simulation docking program MORDOR (MOlecular Recognition with a Driven dynamics OptimizeR)(1) was used to study the structural dynamics of the androgen receptor ligand binding domain (AR LBD) modeled from the static structure of the AR LBD bound to testosterone (T) (PDB ID: 2AM9). The goals of the study were to understand a) the dynamic interaction of the T in its binding pocket, b) AR LBD structural flexibilities that permit T entry/exit from the binding pocket and c) a model of the unliganded AR LBD. Results: Modeling AR LBD structure flexibility over time revealed possible alternative dynamic structures, including those without ligand, overlaid against the canonical nuclear receptor structure. The model dynamically tracks the structural changes as a ligand enters into the ligand binding domain and nestles into the ligand binding pocket. The model predicted the appearance of alpha helices within the AR LBD that transiently fold/unfold during the ligand entry phases. Once in the pocket, the ligand itself remains very dynamic in a still flexible pocket. The model predicted also AR LBD amino acids that sequentially interact with the ligand during its dynamic entry into the AR LBD. Intriguingly, those AR amino acids include those mutated in castration-resistant prostate tumors that continue to grow during androgen suppression therapy. Functional studies showed those mutant ARs had a primary consequence of enhancing response to lower level T, and other androgens, consistent with their role in creating a higher affinity AR that can scavenge low-level androgens in an androgen-suppressed patient. Conclusions: The molecular model of T binding to the AR LBD suggests a degree of structural dynamism not evident in the crystallographic structures commonly associated with nuclear receptors. Some AR mutations activating prostate tumor growth may do so by impacting androgen entry/exit, rather than by altering androgen fit into the ligand binding pocket. Reference: (1) Guilbert C, James TL (2008) J Chem Inf Model. 2008 48(6): 1257-1268. doi: 10.1021/ci8000327

scholarly journals Covalent Modification and Regulation of the Nuclear Receptor Nurr1 by a Dopamine Metabolite

2018 ◽  
Author(s):  
John M. Bruning ◽  
Yan Wang ◽  
Francesca Oltrabella ◽  
Boxue Tian ◽  
Svetlana A. Kholodar ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Ligand Binding ◽  
Nuclear Receptor ◽  
Target Genes ◽  
Cultured Cells ◽  
Binding Pocket ◽  
Regulatory Elements ◽  
Covalent Modification ◽  
X Ray Crystallography

SUMMARYNurr1, a nuclear receptor essential for the development, maintenance, and survival of midbrain dopaminergic neurons, is a potential therapeutic target for Parkinson’s disease, a neurological disorder characterized by the degeneration of these same neurons. Efforts to identify Nurr1 agonists have been hampered by the recognition that it lacks several classic regulatory elements of nuclear receptor function, including the canonical ligand-binding pocket. Here we report that the dopamine metabolite 5,6-dihydroxyindole (DHI) binds directly to and modulates the activity of Nurr1. Using biophysical assays and x-ray crystallography we show that DHI binds to the ligand binding domain within a non-canonical pocket, forming a covalent adduct with Cys566. In cultured cells and zebrafish, DHI stimulates Nurr1 activity, including the transcription of target genes underlying dopamine homeostasis. These findings suggest avenues for developing synthetic Nurr1 ligands to ameliorate the symptoms and progression of Parkinson’s disease.

scholarly journals Hormone receptor 4 is required in muscles and distinct ovarian cell types to regulate specific steps of Drosophila oogenesis

Development ◽  
2021 ◽  
pp. dev.198663
Author(s):  
Lesley N. Weaver ◽  
Daniela Drummond-Barbosa
Keyword(s):  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Hormone Receptor ◽  
Cell Types ◽  
Germline Stem Cell ◽  
Follicle Growth ◽  
Peripheral Tissues ◽  
Ovarian Cell ◽  
Nuclear Receptor Superfamily ◽  
Germline Cyst

The conserved nuclear receptor superfamily has critical roles in many processes, including reproduction. Nuclear receptors with known roles in oogenesis have been studied mostly in the context of their ovary-intrinsic requirement. Recent studies in Drosophila, however, have begun to reveal new roles of nuclear receptor signaling in peripheral tissues in controlling reproduction. Here, we identified Hormone receptor 4 (Hr4) as an oogenesis regulator required in the ovary and muscles. Global Hr4 knockdown leads to increased germline stem cell (GSC) loss, reduced GSC proliferation, early germline cyst death, slowed follicle growth, and vitellogenic follicle degeneration. Tissue-specific knockdown experiments uncovered ovary-intrinsic and peripheral tissue requirements for Hr4. In the ovary, Hr4 is required in the niche for GSC proliferation and in the germline for GSC maintenance. Hr4 functions in muscles to promote GSC maintenance and follicle growth. The specific tissues that require Hr4 for survival of early germline cysts and vitellogenic follicles remain unidentified. These results add to the few examples of muscles controlling gametogenesis and expand our understanding of the complexity of nuclear receptor regulation of various aspects of oogenesis.

scholarly journals The nutrigenomic metabolite L‑carnitine directly modulates the activity and expression of nuclear receptors in adipocytes, liver and muscle cells

2019 ◽  
Author(s):  
Lorenz Förster ◽  
Dominic Indra ◽  
Reinhold Hofbauer
Keyword(s):  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Target Genes ◽  
Muscle Cells ◽  
Carnitine Deficiency ◽  
Mrna Levels ◽  
Carnitine Supplementation ◽  
Short Term ◽  
Protein Activity ◽  
Expression Levels

Abstract Background: L‑carnitine is an indispensable metabolite in eukaryotic cells, which facilitates transport of long‑chain fatty acids into the mitochondrial matrix for subsequent β-oxidation and helps to safeguard the acetyl-CoA level. Additionally, L‑carnitine has been proven to exert a nutrigenomic effect, modulating the expression of numerous target genes. However, the diverging time-dependent effects of short-term and extended L‑carnitine supplementation have not been investigated in more detail yet, especially in the interplay of adipocytes, liver and muscle cells. A cell culture model with conditions of L‑carnitine deficiency and supplementation for these cell types was established to investigate the effects of L‑carnitine on key nuclear receptors and their pathways. Results: L‑carnitine deficiency as well as L‑carnitine supplementation to hepatocytes modulated protein activity of multiple nuclear receptor pathways (RAR, RXR, VDR, PPAR, HNF4, ER, LXR). On the transcriptional level, short‑term L‑carnitine supplementation initially exerted an inhibitory effect on the steady state mRNA levels of PPAR‑α, PPAR‑δ, PPAR-γ, RAR‑β , LXR‑α and RXR‑α in adipocytes, liver and muscle cells. However, extended L‑carnitine supplementation for 24 and 48 hours led to a significant upregulation of PPAR‑α and PPAR‑δ , being key regulators of lipid catabolism, thereby promoting lipolysis and β-oxidation. In addition, significant differences in transcriptional modulation were found between adipocytes, liver and muscle cells. Extended L‑carnitine administration to hepatocytes also modulated mRNA expression levels of nuclear receptor target genes CYP2R1 , ALDH1A1 , HSD11B2 , OGT and HMGCR. Conclusions: These findings show a clear nutrigenomic effect of L‑carnitine on the protein activity and expression levels of selected nuclear receptors in different tissues, promoting lipolytic gene expression as well as decreasing transcription of adipogenic and insulin-resistance linked genes. Therefore L‑carnitine supplementation obviously is a promising strategy supporting established antihyperlipidemic therapies.

scholarly journals Coregulator Function: A Key to Understanding Tissue Specificity of Selective Receptor Modulators

2004 ◽  
Vol 25 (1) ◽  
pp. 45-71 ◽  
Author(s):  
Carolyn L. Smith ◽  
Bert W. O’Malley
Keyword(s):  
Estrogen Receptor ◽  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Critical Role ◽  
Dependent Manner ◽  
Nuclear Receptor Superfamily ◽  
Binding Domains ◽  
Receptor Modulator ◽  
Cellular Environment ◽  
Receptor Modulators

Ligands for the nuclear receptor superfamily control many aspects of biology, including development, reproduction, and homeostasis, through regulation of the transcriptional activity of their cognate receptors. Selective receptor modulators (SRMs) are receptor ligands that exhibit agonistic or antagonistic biocharacter in a cell- and tissue context-dependent manner. The prototypical SRM is tamoxifen, which as a selective estrogen receptor modulator, can activate or inhibit estrogen receptor action. SRM-induced alterations in the conformation of the ligand-binding domains of nuclear receptors influence their abilities to interact with other proteins, such as coactivators and corepressors. It has been postulated, therefore, that the relative balance of coactivator and corepressor expression within a given target cell determines the relative agonist vs. antagonist activity of SRMs. However, recent evidence reveals that the cellular environment also plays a critical role in determining SRM biocharacter. Cellular signaling influences the activity and subcellular localization of coactivators and corepressors as well as nuclear receptors, and this contributes to gene-, cell-, and tissue-specific responses to SRM ligands. Increased understanding of the effect of cellular environment on nuclear receptors and their coregulators has the potential to open the field of SRM discovery and research to many members of the nuclear receptor superfamily.

scholarly journals A Retrospective on Nuclear Receptor Regulation of Inflammation: Lessons from GR and PPARs

PPAR Research ◽  
2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Min-Dian Li ◽  
Xiaoyong Yang
Keyword(s):  
Glucocorticoid Receptor ◽  
Signaling Pathways ◽  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Receptor Regulation ◽  
Peroxisome Proliferator ◽  
Novel Therapies ◽  
Nuclear Receptor Superfamily ◽  
Founding Member ◽  
Peroxisome Proliferator Activated Receptors

Members of the nuclear receptor superfamily have vital roles in regulating immunity and inflammation. The founding member, glucocorticoid receptor (GR), is the prototype to demonstrate immunomodulation via transrepression of the AP-1 and NF-κB signaling pathways. Peroxisome proliferator-activated receptors (PPARs) have emerged as key regulators of inflammation. This review examines the history and current advances in nuclear receptor regulation of inflammation by the crosstalk with AP-1 and NF-κB signaling, focusing on the roles of GR and PPARs. A better understanding of the molecular mechanism by which nuclear receptors inhibit proinflammatory signaling pathways will enable novel therapies to treat chronic inflammation.

P1941The nuclear receptor corepressor 1 blocks CD36-mediated foam cell formation in atherogenesis

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
S Oppi ◽  
S Stein ◽  
V Marzolla ◽  
E Osto ◽  
Z Rancic ◽  
...  
Keyword(s):  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Target Genes ◽  
Foam Cell ◽  
Foam Cell Formation ◽  
High Cholesterol Diet ◽  
Peroxisome Proliferator ◽  
Aortic Sinus ◽  
Protective Function ◽  
Nuclear Receptor Corepressor

Abstract Background Nuclear receptors and their cofactors regulate the expression of various target genes in different tissue and organs to orchestrate downstream (patho)physiological processes. Although the function of several nuclear receptors in atherosclerosis has been studied, very little is known about the role of nuclear receptor cofactors in atherosclerosis. Given its important role to suppress inflammatory processes, we speculated that macrophage nuclear receptor corepressor 1 (NCOR1) plays a protective function in atherosclerosis development. Purpose To evaluate the contribution of macrophage NCOR1 in atherosclerosis we used myeloid cell-specific Ncor1 knockout mice on an atherosclerosis-prone background. Methods and results 8-week-old male and female mice were exposed to a high high-cholesterol diet for 12 weeks. Our findings demonstrate that the lack of macrophage Ncor1 leads to a severe atherosclerotic phenotype in both sexes. These mice show a higher content of plaques along the thoraco-abdominal aortae as well as at the aortic sinus, which were characterized by larger necrotic cores and thinner fibrous caps, a typical signature of unstable plaques. Moreover, we found that the pro-atherogenic effects of the Ncor1 deletion are mediated via derepression of peroxisome proliferator-activated receptor gamma (PPARγ) target genes in mouse and human macrophages, especially the enhanced expression of the CD36 scavenger receptor and the subsequent rise in oxLDL uptake. Interestingly, while the expression of NCOR1 is reduced, the PPARγ signature is increased in human atherosclerotic plaques, and this signature is further pronounced in ruptured compared to stable carotid plaques. Conclusion Our findings suggest that macrophage NCOR1 blocks the pro-atherogenic functions of PPARγ in atherosclerosis and prevents the disease development. Acknowledgement/Funding The Swiss National Science Foundation, the Novartis Foundation, Olga-Mayenfisch Foundation, the OPO foundation

scholarly journals Definition of functionally and structurally distinct repressive states in the nuclear receptor PPARγ

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Zahra Heidari ◽  
Ian M. Chrisman ◽  
Michelle D. Nemetchek ◽  
Scott J. Novick ◽  
Anne-Laure Blayo ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Salt Bridge ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Exchange Mass Spectrometry ◽  
Omega Loop ◽  
Hydrogen Deuterium ◽  
Definition Of

AbstractThe repressive states of nuclear receptors (i.e., apo or bound to antagonists or inverse agonists) are poorly defined, despite the fact that nuclear receptors are a major drug target. Most ligand bound structures of nuclear receptors, including peroxisome proliferator-activated receptor γ (PPARγ), are similar to the apo structure. Here we use NMR, accelerated molecular dynamics and hydrogen-deuterium exchange mass spectrometry to define the PPARγ structural ensemble. We find that the helix 3 charge clamp positioning varies widely in apo and is stabilized by efficacious ligand binding. We also reveal a previously undescribed mechanism for inverse agonism involving an omega loop to helix switch which induces disruption of a tripartite salt-bridge network. We demonstrate that ligand binding can induce multiple structurally distinct repressive states. One state recruits peptides from two different corepressors, while another recruits just one, providing structural evidence of ligand bias in a nuclear receptor.

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