Transcription Shuttling Fats to the Nucleus

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that bind long-chain fatty acids. PPAR functions in control of differentiation in adipocytes and PPARβ regulates differentiation and inflammatory responses in keratinocytes. The PPARs act in the nucleus as transcription factors. However, it has not been clear how lipophilic ligands for these receptors reach the nucleus to bind to the receptors. Tan et al. present evidence that the adipocyte fatty acid-binding protein (A-FABP) and keratinocyte fatty acid-binding protein (K-FABP) bind PPAR ligands and carry them to the nucleus. Transfection of Cos-7 cells with A-FABP or K-FABP increased ligand-induced transcriptional activation by PPAR and PPARβ, respectively. Also, FABPs tagged with green fluorescent protein were translocated to the nucleus in response to ligands that activate PPAR or PPARβ. Thus, the FABPs may act as carriers to deposit ligands that are insoluble in water in the nucleus. Experiments monitoring transfer of a fluorescently labeled ligand between A-FABP and PPAR showed that the process was dependent on the concentrations of the two proteins and thus appeared to be mediated by protein-protein interaction and direct transfer of the ligand from A-FABP to PPAR. This function is similar to the role of cellular retinoic acid-binding protein II in carrying retinoic acid to its nuclear receptor. The authors point out that similar phenotypes in animals or cells lacking K-FABP or A-FABP with animals or cells lacking PPARβ or PPAR, respectively, are consistent with the notion that the described ligand shuttling is important for PPAR function.

N.-S. Tan, N. S. Shaw, N. Vinckenbosch, P. Liu, R. Yasmin, B. Desvergne, W. Wahli, N. Noy, Selective cooperation between fatty acid binding proteins and peroxisome proliferator-activated receptors in regulating transcription. Mol. Cell. Biol. 22, 5114-5127 (2002). [Abstract] [Full Text]