NR4A orphan nuclear receptors influence retinoic acid and docosahexaenoic acid signaling via up-regulation of fatty acid binding protein 5

Biochem Biophys Res Commun. 2009 Dec 25;390(4):1186-91. doi: 10.1016/j.bbrc.2009.10.116. Epub 2009 Oct 25.

Abstract

The orphan nuclear receptor (NR) Nurr1 is expressed in the developing and adult nervous system and is also induced as an immediate early gene in a variety of cell types. In silico analysis of human promoters identified fatty acid binding protein 5 (FABP5), a protein shown to enhance retinoic acid-mediated PPARbeta/delta signaling, as a potential Nurr1 target gene. Nurr1 has previously been implicated in retinoid signaling via its heterodimerization partner RXR. Since NRs are commonly involved in cross-regulatory control we decided to further investigate the regulatory relationship between Nurr1 and FABP5. FABP5 expression was up-regulated by Nurr1 and other NR4A NRs in HEK293 cells, and Nurr1 was shown to activate and bind to the FABP5 promoter, supporting that FABP5 is a direct downstream target of NR4A NRs. We also show that the RXR ligand docosahexaenoic acid (DHA) can induce nuclear translocation of FABP5. Moreover, via up-regulation of FABP5 Nurr1 can enhance retinoic acid-induced signaling of PPARbeta/delta and DHA-induced activation of RXR. We also found that other members of the NR4A orphan NRs can up-regulate FABP5. Thus, our findings suggest that NR4A orphan NRs can influence signaling events of other NRs via control of FABP5 expression levels.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Cell Line
  • Docosahexaenoic Acids / metabolism*
  • Fatty Acid-Binding Proteins / genetics*
  • Gene Expression Regulation*
  • Humans
  • Nuclear Receptor Subfamily 4, Group A, Member 2 / metabolism*
  • PPAR gamma / metabolism
  • PPAR-beta / metabolism
  • Promoter Regions, Genetic
  • Retinoid X Receptor alpha / metabolism
  • Signal Transduction
  • Transcription, Genetic
  • Tretinoin / metabolism*
  • Tretinoin / pharmacology
  • Up-Regulation

Substances

  • FABP5 protein, human
  • Fatty Acid-Binding Proteins
  • NR4A2 protein, human
  • Nuclear Receptor Subfamily 4, Group A, Member 2
  • PPAR gamma
  • PPAR-beta
  • Retinoid X Receptor alpha
  • Docosahexaenoic Acids
  • Tretinoin