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

PLoS Genet. 2015 Jun 1;11(6):e1005213. doi: 10.1371/journal.pgen.1005213. eCollection 2015 Jun.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • COS Cells
  • Chlorocebus aethiops
  • Humans
  • Ligands
  • Memory Disorders / genetics*
  • Mice
  • Molecular Sequence Data
  • Protein Binding
  • Retinoid X Receptors / chemistry
  • Retinoid X Receptors / genetics
  • Retinoid X Receptors / metabolism*
  • Retinol-Binding Proteins, Cellular / genetics
  • Retinol-Binding Proteins, Cellular / metabolism
  • Tretinoin / analogs & derivatives*
  • Tretinoin / metabolism

Substances

  • 13,14-dihydroretinoic acid
  • Ligands
  • Rbp1 protein, mouse
  • Retinoid X Receptors
  • Retinol-Binding Proteins, Cellular
  • Tretinoin

Associated data

  • GEO/GSE48573

Grant support

AK received a PhD fellowship from French Minister of Science, ANC and MWS were supported by the Agence Nationale de la Recherche and Fondation pour la Recherche Médicale, respectively. NR acknowledges the ANR (ANR- 11-BSV8-023) and the French Infrastructure for Integrated Structural Biology (FRISBI). The work was also supported by TÁMOP-4.2.2.A-11/1/KONV-2012-0023 "VÉD-ELEM" project and by the TÁMOP-4.2.2.A-11/1/KONV-2012-0031 project. The project is implemented through the New Hungary Development Plan co-financed by the European Social Fund and the European Regional Development Fund. Work at ARdL laboratory was supported by grants from the Spanish MINECO (SAF2010-17935), Xunta de Galicia (Grant 08CSA052383PR from DXI+D+i; Consolidación 2006/15 from DXPCTSUG; INBIOMED-FEDER "Unha maneira de facer Europa"; Parga Pondal Contract to BV). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.