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42-412: FXR may refer to: Farnesoid X receptor Foxer , a World War II torpedo countermeasure F. X. Reid , pseudonym of British computer science academic Mike W. Shields Topics referred to by the same term [REDACTED] This disambiguation page lists articles associated with the title FXR . If an internal link led you here, you may wish to change

84-495: A conformation of the receptor that preferentially binds coactivator proteins. These proteins often have an intrinsic histone acetyltransferase (HAT) activity, which weakens the association of histones to DNA, and therefore promotes gene transcription. Binding of antagonist ligands to nuclear receptors in contrast induces a conformation of the receptor that preferentially binds corepressor proteins. These proteins, in turn, recruit histone deacetylases (HDACs), which strengthens

126-640: A functional effect is seen in cells because of the large number of intermediate steps between nuclear receptor activation and changes in protein expression levels. However it has been observed that many effects of the application of nuclear hormones, such as changes in ion channel activity, occur within minutes which is inconsistent with the classical mechanism of nuclear receptor action. While the molecular target for these non-genomic effects of nuclear receptors has not been conclusively demonstrated, it has been hypothesized that there are variants of nuclear receptors which are membrane associated instead of being localized in

168-440: A group 2D for which the only member was Drosophila HR78/NR1D1 ( Q24142 ) and orthologues, but it was merged into group 2C later due to high similarity, forming a "group 2C/D". Knockout studies on mice and fruit flies support such a merged group. A topic of debate has been on the identity of the ancestral nuclear receptor as either a ligand-binding or an orphan receptor . This debate began more than twenty-five years ago when

210-497: A number of metabolic intermediates such as fatty acids, bile acids and/or sterols with relatively low affinity. These receptors hence may function as metabolic sensors. Other nuclear receptors, such as CAR and PXR appear to function as xenobiotic sensors up-regulating the expression of cytochrome P450 enzymes that metabolize these xenobiotics. Most nuclear receptors have molecular masses between 50,000 and 100,000 daltons . Nuclear receptors are modular in structure and contain

252-481: A potential mechanism for integrating regulation of development and metabolism by thyroid hormone and receptor tyrosine kinases. In addition, thyroid hormone signaling through PI3K can alter gene expression. The following is a list of the 48 known human nuclear receptors (and their orthologs in other species) categorized according to sequence homology . The list also includes selected family members that lack human orthologs (NRNC symbol highlighted in yellow). Of

294-644: A process known as transrepression . One example of a nuclear receptor that are able to transrepress is the glucocorticoid receptor (GR). Furthermore, certain GR ligands known as Selective Glucocorticoid Receptor Agonists ( SEGRAs ) are able to activate GR in such a way that GR more strongly transrepresses than transactivates. This selectivity increases the separation between the desired antiinflammatory effects and undesired metabolic side effects of these selective glucocorticoids . The classical direct effects of nuclear receptors on gene regulation normally take hours before

336-601: A single tyrosine to phenylalanine substitution in TRβ without disrupting direct gene regulation. When mice were created with this single, conservative amino acid substitution in TRβ, synaptic maturation and plasticity in the hippocampus was impaired almost as effectively as completely blocking thyroid hormone synthesis. This mechanism appears to be conserved in all mammals but not in TRα or any other nuclear receptors. Thus, phosphotyrosine-dependent association of TRβ with PI3K provides

378-494: A single DNA binding domain of the receptor attaching to a single half site HRE. These nuclear receptors are considered orphan receptors , as their endogenous ligands are still unknown. The nuclear receptor/DNA complex then recruits other proteins that transcribe DNA downstream from the HRE into messenger RNA and eventually protein , which causes a change in cell function. Type II receptors, in contrast to type I, are retained in

420-503: A single DNA binding domain of the receptor binds to a single half site HRE. Examples of type IV receptors are found in most of the NR subfamilies. Human nuclear receptors are capable of dimerizing with many other nuclear receptors (homotypic dimerization), as has been shown from large-scale Y2H experiments and text mining efforts of the literature that were focused on specific interactions. Nevertheless, there exists specificity, with members of

462-494: A variable length of DNA, and the second half-site has a sequence inverted from the first (inverted repeat). Type I nuclear receptors include members of subfamily 3, such as the androgen receptor , estrogen receptors , glucocorticoid receptor , and progesterone receptor . It has been noted that some of the NR subfamily 2 nuclear receptors may bind to direct repeat instead of inverted repeat HREs. In addition, some nuclear receptors that bind either as monomers or dimers, with only

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504-578: A variant of type I, and type IV that bind DNA as monomers have also been identified. Accordingly, nuclear receptors may be subdivided into the following four mechanistic classes: Ligand binding to type I nuclear receptors in the cytosol results in the dissociation of heat shock proteins , homo- dimerization , translocation ( i.e. , active transport ) from the cytoplasm into the cell nucleus , and binding to specific sequences of DNA known as hormone response elements (HREs). Type I nuclear receptors bind to HREs consisting of two half-sites separated by

546-490: Is a nuclear receptor that is encoded by the NR1H4 gene in humans. FXR is expressed at high levels in the liver and intestine. Chenodeoxycholic acid and other bile acids are natural ligands for FXR. Similar to other nuclear receptors, when activated, FXR translocates to the cell nucleus , forms a dimer (in this case a heterodimer with RXR ) and binds to hormone response elements on DNA, which up- or down-regulates

588-428: Is normally to upregulate gene expression. This stimulation of gene expression by the ligand is referred to as an agonist response. The agonistic effects of endogenous hormones can also be mimicked by certain synthetic ligands, for example, the glucocorticoid receptor anti-inflammatory drug dexamethasone . Agonist ligands work by inducing a conformation of the receptor which favors coactivator binding (see upper half of

630-441: Is their direct control of genomic DNA. Nuclear receptors play key roles in both embryonic development and adult homeostasis. As discussed below, nuclear receptors are classified according to mechanism or homology . Nuclear receptors are specific to metazoans (animals) and are not found in protists , algae , fungi , or plants. Amongst the early-branching animal lineages with sequenced genomes, two have been reported from

672-606: The sponge Amphimedon queenslandica , two from the comb jelly Mnemiopsis leidyi four from the placozoan Trichoplax adhaerens and 17 from the cnidarian Nematostella vectensis . There are 270 nuclear receptors in the roundworm Caenorhabditis elegans alone, 21 in the fruit fly and other insects, 73 in zebrafish . Humans, mice, and rats have respectively 48, 49, and 47 nuclear receptors each. Ligands that bind to and activate nuclear receptors include lipophilic substances such as endogenous hormones , vitamins A and D , and xenobiotic hormones . Because

714-622: The FXR to regulate the expression and activity of epithelial transport proteins involved in fluid homeostasis in the intestine, such as the cystic fibrosis transmembrane conductance regulator (CFTR). Activation of FXR in diabetic mice reduces plasma glucose and improves insulin sensitivity , whereas inactivation of FXR has the opposite effect. Farnesoid X receptor has been shown to interact with: A number of ligands for FXR are known, of both natural and synthetic origin. Nuclear receptor Nuclear receptors bind directly to DNA regulating

756-596: The NR/DNA complex that transcribe DNA into messenger RNA. Type II nuclear receptors include principally subfamily 1, for example the retinoic acid receptor , retinoid X receptor and thyroid hormone receptor . Type III nuclear receptors (principally NR subfamily 2) are similar to type I receptors in that both classes bind to DNA as homodimers. However, type III nuclear receptors, in contrast to type I, bind to direct repeat instead of inverted repeat HREs. Type IV nuclear receptors bind either as monomers or dimers, but only

798-619: The absence of ligand. Small lipophilic substances such as natural hormones diffuse through the cell membrane and bind to nuclear receptors located in the cytosol (type I NR) or nucleus (type II NR) of the cell. Binding causes a conformational change in the receptor which, depending on the class of receptor, triggers a cascade of downstream events that direct the NRs to DNA transcription regulation sites which result in up or down-regulation of gene expression. They generally function as homo/heterodimers. In addition, two additional classes, type III which are

840-756: The activity of the endogenous hormones cortisol and progesterone respectively. Antagonist ligands work by inducing a conformation of the receptor which prevents coactivator binding, and promotes corepressor binding (see lower half of the figure to the right). Finally, some nuclear receptors promote a low level of gene transcription in the absence of agonists (also referred to as basal or constitutive activity). Synthetic ligands which reduce this basal level of activity in nuclear receptors are known as inverse agonists . A number of drugs that work through nuclear receptors display an agonist response in some tissues and an antagonistic response in other tissues. This behavior may have substantial benefits since it may allow retaining

882-466: The association of histones to DNA, and therefore represses gene transcription. Depending on the receptor involved, the chemical structure of the ligand and the tissue that is being affected, nuclear receptor ligands may display dramatically diverse effects ranging in a spectrum from agonism to antagonism to inverse agonism. The activity of endogenous ligands (such as the hormones estradiol and testosterone ) when bound to their cognate nuclear receptors

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924-404: The chemical structure of the ligand and the receptor involved, however it is thought that many SRMs work by promoting a conformation of the receptor that is closely balanced between agonism and antagonism. In tissues where the concentration of coactivator proteins is higher than corepressors , the equilibrium is shifted in the agonist direction. Conversely in tissues where corepressors dominate,

966-403: The cytosol or nucleus. Furthermore, these membrane associated receptors function through alternative signal transduction mechanisms not involving gene regulation. While it has been hypothesized that there are several membrane associated receptors for nuclear hormones, many of the rapid effects have been shown to require canonical nuclear receptors. However, testing the relative importance of

1008-439: The desired beneficial therapeutic effects of a drug while minimizing undesirable side effects. Drugs with this mixed agonist/antagonist profile of action are referred to as selective receptor modulators (SRMs). Examples include Selective Androgen Receptor Modulators ( SARMs ), Selective Estrogen Receptor Modulators ( SERMs ) and Selective Progesterone Receptor Modulators ( SPRMs ). The mechanism of action of SRMs may vary depending on

1050-483: The emergence of a new hypothesis regarding the ancestral state of the nuclear receptor. This hypothesis suggests that the ancestral receptor may act as a lipid sensor with an ability to bind, albeit rather weakly, several different hydrophobic molecules such as, retinoids, steroids, hemes, and fatty acids. With its ability to interact with a variety of compounds, this receptor, through duplications, would either lose its ability for ligand-dependent activity, or specialize into

1092-575: The expression of a large number of genes is regulated by nuclear receptors, ligands that activate these receptors can have profound effects on the organism. Many of these regulated genes are associated with various diseases, which explains why the molecular targets of approximately 13% of U.S. Food and Drug Administration (FDA) approved drugs target nuclear receptors. A number of nuclear receptors, referred to as orphan receptors , have no known (or at least generally agreed upon) endogenous ligands. Some of these receptors such as FXR , LXR , and PPAR bind

1134-504: The expression of adjacent genes; hence these receptors are classified as transcription factors . The regulation of gene expression by nuclear receptors often occurs in the presence of a ligand —a molecule that affects the receptor's behavior. Ligand binding to a nuclear receptor results in a conformational change activating the receptor. The result is up- or down-regulation of gene expression. A unique property of nuclear receptors that differentiates them from other classes of receptors

1176-487: The expression of certain genes . One of the primary functions of FXR activation is the suppression of cholesterol 7 alpha-hydroxylase (CYP7A1), the rate-limiting enzyme in bile acid synthesis from cholesterol . FXR does not directly bind to the CYP7A1 promoter. Rather, FXR induces expression of small heterodimer partner (SHP), which then functions to inhibit transcription of the CYP7A1 gene. FXR likewise stimulates

1218-469: The figure to the right). Other synthetic nuclear receptor ligands have no apparent effect on gene transcription in the absence of endogenous ligand. However they block the effect of agonist through competitive binding to the same binding site in the nuclear receptor. These ligands are referred to as antagonists. An example of antagonistic nuclear receptor drug is mifepristone which binds to the glucocorticoid and progesterone receptors and therefore blocks

1260-523: The first ligands were identified as mammalian steroid and thyroid hormones. Shortly thereafter, the identification of the ecdysone receptor in Drosophila introduced the idea that nuclear receptors were hormonal receptors that bind ligands with a nanomolar affinity. At the time, the three known nuclear receptor ligands were steroids, retinoids, and thyroid hormone, and of those three, both steroids and retinoids were products of terpenoid metabolism. Thus, it

1302-755: The following domains : The DNA-binding (C), and ligand binding (E) domains are independently well folded and structurally stable while the N-terminal (A/B), hinge region (D) and optional C-terminal (F) domains may be conformationally flexible and disordered. Domains relative orientations are very different by comparing three known multi-domain crystal structures, two of them binding on DR1 (DBDs separated by 1 bp), one binding on DR4 (by 4 bp). Nuclear receptors are multifunctional proteins that transduce signals of their cognate ligands . Nuclear receptors (NRs) may be classified into two broad classes according to their mechanism of action and subcellular distribution in

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1344-435: The genomic and nongenomic mechanisms in vivo has been prevented by the absence of specific molecular mechanisms for the nongenomic effects that could be blocked by mutation of the receptor without disrupting its direct effects on gene expression. A molecular mechanism for non-genomic signaling through the nuclear thyroid hormone receptor TRβ involves the phosphatidylinositol 3-kinase ( PI3K ). This signaling can be blocked by

1386-433: The ligand behaves as an antagonist. The most common mechanism of nuclear receptor action involves direct binding of the nuclear receptor to a DNA hormone response element. This mechanism is referred to as transactivation . However some nuclear receptors not only have the ability to directly bind to DNA, but also to other transcription factors. This binding often results in deactivation of the second transcription factor in

1428-1005: The link to point directly to the intended article. Retrieved from " https://en.wikipedia.org/w/index.php?title=FXR&oldid=932834489 " Category : Disambiguation pages Hidden categories: Short description is different from Wikidata All article disambiguation pages All disambiguation pages Farnesoid X receptor 1OSH , 3BEJ , 3DCT , 3DCU , 3FLI , 3FXV , 3GD2 , 3HC5 , 3HC6 , 3L1B , 3OKH , 3OKI , 3OLF , 3OMK , 3OMM , 3OOF , 3OOK , 3RUT , 3RUU , 3RVF , 3P88 , 3P89 , 4OIV , 4WVD , 4QE6 , 4QE8 9971 20186 ENSG00000012504 ENSMUSG00000047638 Q96RI1 Q60641 NM_005123 NM_001163504 NM_001163700 NM_009108 NM_001385711 NP_005114 NP_001193906.1 NP_001193908.1 NP_001156976 NP_001157172 NP_033134 NP_001372640 The bile acid receptor ( BAR ), also known as farnesoid X receptor ( FXR ) or NR1H4 (nuclear receptor subfamily 1, group H, member 4),

1470-406: The nucleus regardless of the ligand binding status and in addition bind as hetero-dimers (usually with RXR ) to DNA. In the absence of ligand, type II nuclear receptors are often complexed with corepressor proteins. Ligand binding to the nuclear receptor causes dissociation of corepressor and recruitment of coactivator proteins. Additional proteins including RNA polymerase are then recruited to

1512-525: The same subfamily having very similar NR dimerization partners and the underlying dimerization network has certain topological features, such as the presence of highly connected hubs (RXR and SHP). Nuclear receptors bound to hormone response elements recruit a significant number of other proteins (referred to as transcription coregulators ) that facilitate or inhibit the transcription of the associated target gene into mRNA. The function of these coregulators are varied and include chromatin remodeling (making

1554-498: The spontaneous development of liver tumors . Reducing the pool of bile acids in the FXR mice by feeding the bile acid sequestering resin cholestyramine reduced the number and size of the malignant lesions. FXR has also been found to be important in regulation of hepatic triglyceride levels. Specifically, FXR activation suppresses lipogenesis and promotes free fatty acid oxidation by PPARα activation. Studies have also shown

1596-410: The synthesis of fibroblast growth factor 19 , which also inhibits expression of CYP7A1 and sterol 12-alpha-hydroxylase ( CYP8B1 ) via fibroblast growth factor receptor 4 . In this way, a negative feedback pathway is established in which synthesis of bile acids is inhibited when cellular levels are already high. The absence of FXR in an FXR mouse model led to increased bile acids in the liver, and

1638-403: The target gene either more or less accessible to transcription) or a bridging function to stabilize the binding of other coregulatory proteins. Nuclear receptors may bind specifically to a number of coregulator proteins, and thereby influence cellular mechanisms of signal transduction both directly, as well as indirectly. Binding of agonist ligands (see section below) to nuclear receptors induces

1680-434: The two 0-families, 0A has a family 1-like DBD, and 0B has a unique LBD. The second DBD of family 7 is probably related to the family 1 DBD. Three probably family-1 NRs from Biomphalaria glabrata possess a DBD along with a family 0B-like LBD. The placement of C. elegans nhr-1 ( Q21878 ) is disputed: although most sources place it as NR1K1, manual annotation at WormBase considers it a member of NR2A. There used to be

1722-502: Was postulated that ancestral receptor would have been liganded by a terpenoid molecule. In 1992, a comparison of the DNA-binding domain of all known nuclear receptors led to the construction of a phylogenic tree of nuclear receptor that indicated that all nuclear receptors shared a common ancestor. As a result, there was an increased effort upon uncovering the state of the first nuclear receptor, and by 1997 an alternative hypothesis

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1764-446: Was suggested: the ancestral nuclear receptor was an orphan receptor and it acquired ligand-binding ability over time This hypothesis was proposed based on the following arguments: Over the next 10 years, experiments were conducted to test this hypothesis and counterarguments soon emerged: A combination of this recent evidence, as well as an in-depth study of the physical structure of the nuclear receptor ligand binding domain has led to

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