9-cis-13,14-Dihydroretinoic Acid Is an Endogenous Retinoid Acting as RXR Ligand in Mice

Autor: Natacha Rochel, Susana Alvarez, Monika Szklenar, Angel R. de Lera, Laszlo Nagy, Wojciech Krezel, Ralph Rühl, Marta Wietrzych-Schindler, Anna Niewiadomska-Cimicka, Agnieszka Krzyżosiak, Belén Vaz, Lajos Széles
Přispěvatelé: Peney, Maité, Department of Biochemistry and Molecular Biology, Faculty of Medicine, Debrecen, Hungary, Paprika Bioanalytics BT, Debrecen, Hungary., Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), DE-MTA 'Lendület' Immunogenomics Research Group, University of Debrecen, Debrecen, Hungary., Universidade de Vigo
Jazyk: angličtina
Rok vydání: 2015
Předmět:
Zdroj: PLoS Genetics
PLoS Genetics, 2015, 11 (6), pp.e1005213. ⟨10.1371/journal.pgen.1005213⟩
PLoS Genetics, Vol 11, Iss 6, p e1005213 (2015)
'PLoS Genetics ', vol: 11, pages: e1005213-1-e1005213-16 (2015)
ISSN: 1553-7390
1553-7404
Popis: The retinoid X receptors (RXRs) are ligand-activated transcription factors which heterodimerize with a number of nuclear hormone receptors, thereby controlling a variety of (patho)-physiological processes. Although synthetic RXR ligands are developed for the treatment of various diseases, endogenous ligand(s) for these receptors have not been conclusively identified. We show here that mice lacking cellular retinol binding protein (Rbp1-/-) display memory deficits reflecting compromised RXR signaling. Using HPLC-MS and chemical synthesis we identified in Rbp1-/- mice reduced levels of 9-cis-13,14-dihydroretinoic acid (9CDHRA), which acts as an RXR ligand since it binds and transactivates RXR in various assays. 9CDHRA rescues the Rbp1-/- phenotype similarly to a synthetic RXR ligand and displays similar transcriptional activity in cultured human dendritic cells. High endogenous levels of 9CDHRA in mice indicate physiological relevance of these data and that 9CDHRA acts as an endogenous RXR ligand.
Author Summary Daily nutrition, in addition to being a source of energy, contains micronutrients, a class of nutrients including vitamins which are essential for life and which act by orchestrating a vast number of developmental and physiological processes. During metabolism, micronutrients are frequently transformed into their bioactive forms. Nuclear hormone receptors are a family of proteins functioning as ligand-regulated transcription factors which can sense such bioactive molecules and translate those signals into transcriptional, adaptive responses. Retinoid X receptors occupy a central place in this signaling as they directly interact, and thereby control, activities of several nuclear hormone receptors. We report here the identification of a novel bioactive form of vitamin A, which is the first endogenous form of this vitamin capable to bind and activate retinoid X receptors. Accordingly, we show that this single molecule displays biological activity similar to synthetic agonists of retinoid X receptors and coordinates transcriptional activities of several nuclear receptor signaling pathways. Those findings may have immediate biomedical implications, as retinoid X receptors are implicated in the control of a number of physiological functions and their pathology.
Databáze: OpenAIRE
Externí odkaz: