TY - JOUR
T1 - 9-cis-13,14-Dihydroretinoic Acid Is an Endogenous Retinoid Acting as RXR Ligand in Mice
AU - Rühl, Ralph
AU - Krzyżosiak, Agnieszka
AU - Niewiadomska-Cimicka, Anna
AU - Rochel, Natacha
AU - Szeles, Lajos
AU - Vaz, Belén
AU - Wietrzych-Schindler, Marta
AU - Álvarez, Susana
AU - Szklenar, Monika
AU - Nagy, Laszlo
AU - de Lera, Angel R.
AU - Krężel, Wojciech
N1 - Publisher Copyright:
© 2015 Rühl et al.
PY - 2015/7/1
Y1 - 2015/7/1
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.pgen.1005213
DO - 10.1371/journal.pgen.1005213
M3 - Article
C2 - 26030625
AN - SCOPUS:84937776226
SN - 1553-7390
VL - 11
JO - PLoS genetics
JF - PLoS genetics
IS - 6
M1 - e1005213
ER -