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One of the pathways taken in multicellular organisms to process extracellular signals into a transcriptional response within a target cell is via a nuclear receptor. These receptors are transcription factors that become active after binding to their cognate ligands. The ligands are small lipophilic molecules which include the steroid/thyroid hormones and the fat soluble vitamins A and D. The receptors belong to a highly conserved superfamily of proteins which have similar structural and functional domains. Genetic analyses of these receptors have led to the unexpected discovery that several other receptor-like proteins exist for which a ligand (i.e., hormone) is not known. Since these proteins, referred to as orphan receptors, have the potential to interact with known hormone receptor pathways or function on their own as ligand-dependent transcription factors, their investigation - and the hunt for their ligands - has become a major research interest.

A growing body of evidence suggests that many of the orphan nuclear receptors evolved as sensors to protect cells from elevated levels of potentially harmful lipids, including cholesterol, bile acids, fatty acids, and many xenobiotics. Nuclear receptors that have been shown to function as lipid sensors include the oxysterol receptors (LXRα and β), the bile acid receptor (FXR), and the xenobiotic receptor (PXR). The analysis of these receptors has led to the identification of a lipid metabolic cascade that is regulated by the lipid binding to its nuclear receptor and activating transcription of at least three families of proteins. These families include cytochrome P450 enzymes that catabolize the lipid, intracellular binding proteins that buffer the lipid in cells, and ATP-binding cassette transporters that move lipids out of cells. In this way, the lipid-sensing receptors feed-forward activate the metabolic network that maintains homeostatic levels of dietary lipids. Our newest studies suggest that this lipid-sensing paradigm may be extended to other members of the nuclear receptor family, and in particular to receptors that have traditionally been thought to have other functions.

One such example is the vitamin D receptor (VDR). In addition to binding vitamin D and regulating calcium homeostasis, the VDR has evolved the ability to protect the body against colon cancer by sensing and eliminating the carcinogenic bile acid, lithocholic acid. Taken together, the finding that this class of receptors function as key regulators of cholesterol and bile acid homeostasis has important therapeutic implications for the discovery of drugs targeted against these receptors.

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