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

• Main Authors: Ralph Rühl, Agnieszka Krzyżosiak, Anna Niewiadomska-Cimicka, Natacha Rochel, Lajos Szeles, Belén Vaz, Marta Wietrzych-Schindler, Susana Álvarez, Monika Szklenar, Laszlo Nagy, Angel R de Lera, Wojciech Krężel
• Format: Article
• Language: English
• Published: Public Library of Science (PLoS) 2015-06-01
• Series: PLoS Genetics
• Online Access: http://europepmc.org/articles/PMC4451509?pdf=render

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.