Potential endogenous lipid ligands for the nuclear receptor transcription factor Steroidogenic Factor-1

Nuclear receptors are lipid-regulated transcription factors that respond to the changing metabolic and signaling requirements of animal cells and tissues. Steroidogenic Factor 1 (SF-1, NR5A1) is a nuclear receptor and master regulator of steroidogenic gene expression. SF-1 is required for development and adult function of steroidogenic tissues, hyperactivation of SF-1 associates with adrenocortical carcinoma, while hypomorphic loss-of-function polymorphisms associate with disorders of sexual development. Many of these physiological functions of SF-1 are broadly understood, however the identity of the endogenous regulatory lipid ligands for SF-1 have yet to be well established, preventing progress on therapeutic development for human diseases, such as adrenocortical carcinoma. Several signaling lipids have been put forth as potential regulatory ligands of SF-1, including sphingosine, lyso-sphingomyelin, sphingomyelin, ceramide and several phosphoinositide species including PI(4,5)P2 and PI(3,4,5)P3. Here, we review the evidence linking the ability of these potential phospholipid ligands to regulate SF-1 mediated gene expression in metazoan cells, and discuss how lipid ligands regulate SF-1 from a structural perspective.