Research ArticleBiochemistry

Endogenous retinoid X receptor ligands in mouse hematopoietic cells

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Sci. Signal.  31 Oct 2017:
Vol. 10, Issue 503, eaan1011
DOI: 10.1126/scisignal.aan1011

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Endogenous RXRA ligands in hematopoietic cells

Like other nuclear receptors, retinoid X receptor α (RXRA) stimulates the transcription of target genes in a ligand-dependent manner. Both vitamin A–derived retinoic acids and fatty acids have been implicated as endogenous ligands for RXRA. Using a reporter system for detecting RXRA activation in vivo, Niu et al. found that RXRA activity increased in hematopoietic cells when mice were subjected to treatments that stimulated myeloid cells. Plasma from these mice also stimulated RXRA activation, even if the mice were deficient in vitamin A but not if the mice were deficient in fatty acids. Mass spectrometry and other biochemical methods identified the long-chain fatty acid C24:5 as the most likely endogenous ligand for RXRA in this context. These findings establish fatty acids as dynamically controlled natural ligands for RXRA in hematopoietic cells.

Abstract

The retinoid X receptor α (RXRA) has been implicated in diverse hematological processes. To identify natural ligands of RXRA that are present in hematopoietic cells, we adapted an upstream activation sequence–green fluorescent protein (UAS-GFP) reporter mouse to detect natural RXRA ligands in vivo. We observed reporter activity in diverse types of hematopoietic cells in vivo. Reporter activity increased during granulocyte colony-stimulating factor (G-CSF)–induced granulopoiesis and after phenylhydrazine (PHZ)–induced anemia, suggesting the presence of dynamically regulated natural RXRA ligands in hematopoietic cells. Mouse plasma activated Gal4-UAS reporter cells in vitro, and plasma from mice treated with G-CSF or PHZ recapitulated the patterns of reporter activation that we observed in vivo. Plasma from mice with dietary vitamin A deficiency only mildly reduced RXRA reporter activity, whereas plasma from mice on a fatty acid restriction diet reduced reporter activity, implicating fatty acids as plasma RXRA ligands. Through differential extraction coupled with mass spectrometry, we identified the long-chain fatty acid C24:5 as a natural RXRA ligand that was greatly increased in abundance in response to hematopoietic stress. Together, these data suggest that natural RXRA ligands are present and dynamically increased in abundance in mouse hematopoietic cells in vivo.

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