Nuclear receptors as drug targets for metabolic disease.
Nuclear hormone receptors comprise a superfamily of ligand-activated transcription factors that control development, differentiation, and homeostasis. Over the last 15 years a growing number of nuclear receptors have been identified that coordinate genetic networks regulating lipid metabolism and energy utilization. Several of these receptors directly sample the levels of metabolic intermediates including fatty acids and cholesterol derivatives and use this information to regulate the synthesis, transport, and breakdown of the metabolite of interest. In contrast, other family members sense metabolic activity via the presence or absence of interacting proteins. The ability of these nuclear receptors to impact metabolism will be discussed and the challenges facing drug discovery efforts for this class of targets will be highlighted.
Schulman
Ira G
IG
Center for Molecular Design and Department of Pharmacology, University of Virginia Health System, 1340 Jefferson Park Avenue, Charlottesville, VA 22908, USA. igs4c@virginia.edu
D000818:Animals; D055808:Drug Discovery; D004734:Energy Metabolism; D006801:Humans; D008024:Ligands; D050356:Lipid Metabolism; D000071518:Liver X Receptors; D008659:Metabolic Diseases / Q000188:drug therapy* / Q000378:metabolism*; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000139:chemically induced; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
D008024:Ligands; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D047492:Peroxisome Proliferator-Activated Receptors; D018160:Receptors, Cytoplasmic and Nuclear