Related Research Articles
In the field of molecular biology, the peroxisome proliferator–activated receptors (PPARs) are a group of nuclear receptor proteins that function as transcription factors regulating the expression of genes. PPARs play essential roles in the regulation of cellular differentiation, development, and metabolism, and tumorigenesis of higher organisms.
The retinoids are a class of chemical compounds that are natural derivatives of vitamin A or are chemically related to it. Synthetic retinoids are used in medicine where they regulate skin health, immunity and bone disorders.
Retinoic acid (simplified nomenclature for all-trans-retinoic acid) is a metabolite of vitamin A1 (all-trans-retinol) that is required for embryonic development, male fertility, regulation of bone growth and immune function. All-trans-retinoic acid is required for chordate animal development, which includes all higher animals from fish to humans. During early embryonic development, all-trans-retinoic acid generated in a specific region of the embryo helps determine position along the embryonic anterior/posterior axis by serving as an intercellular signaling molecule that guides development of the posterior portion of the embryo. It acts through Hox genes, which ultimately control anterior/posterior patterning in early developmental stages. In adult tissues, the activity of endogenous retinoic acid appears limited to immune function. and male fertility. Retinoic acid administered as a drug (see tretinoin and alitretinoin) causes significant toxicity that is distinct from normal retinoid biology.
The thyroid hormone receptor (TR) is a type of nuclear receptor that is activated by binding thyroid hormone. TRs act as transcription factors, ultimately affecting the regulation of gene transcription and translation. These receptors also have non-genomic effects that lead to second messenger activation, and corresponding cellular response.
The retinoic acid receptor (RAR) is a type of nuclear receptor which can also act as a ligand-activated transcription factor that is activated by both all-trans retinoic acid and 9-cis retinoic acid, retinoid active derivatives of Vitamin A. They are typically found within the nucleus. There are three retinoic acid receptors (RAR), RAR-alpha, RAR-beta, and RAR-gamma, encoded by the RARA, RARB, RARG genes, respectively. Within each RAR subtype there are various isoforms differing in their N-terminal region A. Multiple splice variants have been identified in human RARs: four for RARA, five for RARB, and two for RARG. As with other type II nuclear receptors, RAR heterodimerizes with RXR and in the absence of ligand, the RAR/RXR dimer binds to hormone response elements known as retinoic acid response elements (RAREs) complexed with corepressor protein. Binding of agonist ligands to RAR results in dissociation of corepressor and recruitment of coactivator protein that, in turn, promotes transcription of the downstream target gene into mRNA and eventually protein. In addition, the expression of RAR genes is under epigenetic regulation by promoter methylation. Both the length and magnitude of the retinoid response is dependent of the degradation of RARs and RXRs through the ubiquitin-proteasome. This degradation can lead to elongation of the DNA transcription through disruption of the initiation complex or to end the response to facilitate further transcriptional programs. RAR receptors are also known to exhibit many retinoid-independent effects as they bind to and regulate other nuclear receptor pathways, such as the estrogen receptor.
The liver X receptor (LXR) is a member of the nuclear receptor family of transcription factors and is closely related to nuclear receptors such as the PPARs, FXR and RXR. Liver X receptors (LXRs) are important regulators of cholesterol, fatty acid, and glucose homeostasis. LXRs were earlier classified as orphan nuclear receptors, however, upon discovery of endogenous oxysterols as ligands they were subsequently deorphanized.
In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroids, thyroid hormones, vitamins, and certain other molecules. These intracellular receptors work with other proteins to regulate the expression of specific genes, thereby controlling the development, homeostasis, and metabolism of the organism.
The nuclear receptor co-repressor 1 also known as thyroid-hormone- and retinoic-acid-receptor-associated co-repressor 1 (TRAC-1) is a protein that in humans is encoded by the NCOR1 gene.
The small heterodimer partner (SHP) also known as NR0B2 is a protein that in humans is encoded by the NR0B2 gene. SHP is a member of the nuclear receptor family of intracellular transcription factors. SHP is unusual for a nuclear receptor in that it lacks a DNA binding domain. Therefore, it is technically neither a transcription factor nor nuclear receptor but nevertheless it is still classified as such due to relatively high sequence homology with other nuclear receptor family members.
Peroxisome proliferator-activated receptor gamma, also known as the glitazone reverse insulin resistance receptor, or NR1C3 is a type II nuclear receptor functioning as a transcription factor that in humans is encoded by the PPARG gene.
Retinoid X receptor alpha (RXR-alpha), also known as NR2B1 is a nuclear receptor that in humans is encoded by the RXRA gene.
Peroxisome proliferator-activated receptor alpha (PPAR-α), also known as NR1C1, is a nuclear receptor protein functioning as a transcription factor that in humans is encoded by the PPARA gene. Together with peroxisome proliferator-activated receptor delta and peroxisome proliferator-activated receptor gamma, PPAR-alpha is part of the subfamily of peroxisome proliferator-activated receptors. It was the first member of the PPAR family to be cloned in 1990 by Stephen Green and has been identified as the nuclear receptor for a diverse class of rodent hepatocarcinogens that causes proliferation of peroxisomes.
Retinoic acid receptor alpha (RAR-α), also known as NR1B1, is a nuclear receptor that in humans is encoded by the RARA gene.
Liver X receptor alpha (LXR-alpha) is a nuclear receptor protein that in humans is encoded by the NR1H3 gene.
Retinoid X receptor gamma (RXR-gamma), also known as NR2B3 is a nuclear receptor that in humans is encoded by the RXRG gene.
Retinoid X receptor beta (RXR-beta), also known as NR2B2 is a nuclear receptor that in humans is encoded by the RXRB gene.
Retinoic acid receptor gamma (RAR-γ), also known as NR1B3 is a nuclear receptor encoded by the RARG gene. Adapalene selectively targets retinoic acid receptor beta and retinoic acid receptor gamma and its agonism of the gamma subtype is largely responsible for adapalene's observed effects.
Liver X receptor beta (LXR-β) is a member of the nuclear receptor family of transcription factors. LXR-β is encoded by the NR1H2 gene.
RAR-related orphan receptor gamma (RORγ) is a protein that in humans is encoded by the RORC gene. RORγ is a member of the nuclear receptor family of transcription factors. It is mainly expressed in immune cells and it also regulates circadian rhythms. It may be involved in the progression of certain types of cancer.
PPAR agonists are drugs which act upon the peroxisome proliferator-activated receptor. They are used for the treatment of symptoms of the metabolic syndrome, mainly for lowering triglycerides and blood sugar.
References
- ↑ Germain P, Chambon P, Eichele G, Evans RM, Lazar MA, Leid M, et al. (December 2006). "International Union of Pharmacology. LXIII. Retinoid X receptors". Pharmacological Reviews. 58 (4): 760–772. doi:10.1124/pr.58.4.7. PMID 17132853. S2CID 1476000.
- ↑ de Lera ÁR, Krezel W, Rühl R (May 2016). "An Endogenous Mammalian Retinoid X Receptor Ligand, At Last!". ChemMedChem. 11 (10): 1027–1037. doi:10.1002/cmdc.201600105. PMID 27151148. S2CID 269196.
- ↑ Allenby G, Bocquel MT, Saunders M, Kazmer S, Speck J, Rosenberger M, et al. (January 1993). "Retinoic acid receptors and retinoid X receptors: interactions with endogenous retinoic acids". Proceedings of the National Academy of Sciences of the United States of America. 90 (1): 30–34. Bibcode:1993PNAS...90...30A. doi: 10.1073/pnas.90.1.30 . PMC 45593 . PMID 8380496.
- ↑ Rühl R, Krzyżosiak A, Niewiadomska-Cimicka A, Rochel N, Szeles L, Vaz B, et al. (June 2015). "9-cis-13,14-Dihydroretinoic Acid Is an Endogenous Retinoid Acting as RXR Ligand in Mice". PLOS Genetics. 11 (6): e1005213. doi: 10.1371/journal.pgen.1005213 . PMC 4451509 . PMID 26030625.
- ↑ Panchal MR, Scarisbrick JJ (2015-02-03). "The utility of bexarotene in mycosis fungoides and Sézary syndrome". OncoTargets and Therapy. 8: 367–373. doi: 10.2147/OTT.S61308 . PMC 4322887 . PMID 25678803.
- ↑ Plutzky J (April 2011). "The PPAR-RXR transcriptional complex in the vasculature: energy in the balance". Circulation Research. 108 (8): 1002–1016. doi: 10.1161/CIRCRESAHA.110.226860 . PMID 21493923.
- ↑ Krezel W, Dupé V, Mark M, Dierich A, Kastner P, Chambon P (August 1996). "RXR gamma null mice are apparently normal and compound RXR alpha +/-/RXR beta -/-/RXR gamma -/- mutant mice are viable". Proceedings of the National Academy of Sciences of the United States of America. 93 (17): 9010–9014. doi: 10.1073/pnas.93.17.9010 . PMC 38586 . PMID 8799145.
- ↑ Haugen BR, Jensen DR, Sharma V, Pulawa LK, Hays WR, Krezel W, et al. (August 2004). "Retinoid X receptor gamma-deficient mice have increased skeletal muscle lipoprotein lipase activity and less weight gain when fed a high-fat diet". Endocrinology. 145 (8): 3679–3685. doi:10.1210/en.2003-1401. PMID 15087432.
- ↑ Esposito M, Amory JK, Kang Y (September 2024). "The pathogenic role of retinoid nuclear receptor signaling in cancer and metabolic syndromes". The Journal of Experimental Medicine. 221 (9). doi:10.1084/jem.20240519. PMID 39133222.
