Saturated fatty acids regulate retinoic acid signalling and suppress tumorigenesis by targeting fatty acid-binding protein 5

Nat Commun. 2015 Nov 23:6:8794. doi: 10.1038/ncomms9794.

Abstract

Long chain fatty acids (LCFA) serve as energy sources, components of cell membranes and precursors for signalling molecules. Here we show that these biological compounds also regulate gene expression and that they do so by controlling the transcriptional activities of the retinoic acid (RA)-activated nuclear receptors RAR and PPARβ/δ. The data indicate that these activities of LCFA are mediated by FABP5, which delivers ligands from the cytosol to nuclear PPARβ/δ. Both saturated and unsaturated LCFA (SLCFA, ULCFA) bind to FABP5, thereby displacing RA and diverting it to RAR. However, while SLCFA inhibit, ULCFA activate the FABP5/PPARβ/δ pathway. We show further that, by concomitantly promoting the activation of RAR and inhibiting the activation of PPARβ/δ, SLCFA suppress the oncogenic properties of FABP5-expressing carcinoma cells in cultured cells and in vivo. The observations suggest that compounds that inhibit FABP5 may constitute a new class of drugs for therapy of certain types of cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinogenesis / genetics
  • Carcinogenesis / metabolism
  • Cell Line, Tumor
  • Down-Regulation
  • Fatty Acid-Binding Proteins / genetics
  • Fatty Acid-Binding Proteins / metabolism*
  • Fatty Acids / metabolism*
  • Humans
  • PPAR delta / genetics
  • PPAR delta / metabolism
  • PPAR-beta / genetics
  • PPAR-beta / metabolism
  • Receptors, Retinoic Acid / genetics
  • Receptors, Retinoic Acid / metabolism
  • Signal Transduction*
  • Tretinoin / metabolism*

Substances

  • FABP5 protein, human
  • Fatty Acid-Binding Proteins
  • Fatty Acids
  • PPAR delta
  • PPAR-beta
  • Receptors, Retinoic Acid
  • Tretinoin