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Lipids as Ligands for Orphan Nuclear Receptors

Nuclear Receptors are a family of 48 transcription factors, many of which are regulated by small lipophilic molecules such as steroid hormones and metabolites of vitamins A and D. We have been especially interested in the biological function of the orphan nuclear receptors and their potential use as molecular targets for drug discovery. During characterization of these orphan receptors, we have identified many lipid components as endogenous ligands. Examples include fatty acids (PPAR, HNF4, RXR), cholesterol (LXR, ROR), bile acids (FXR), and phospholipids (LRH1/SF1). The binding characteristics of these lipid ligands have been studied by X‐ray crystallography and in many cases small synthetic ligands have been designed to regulate receptor activity.