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 led to the unexpected discovery that several other receptor-like proteins exist for which ligands (e.g., hormones) are 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 by our laboratory to function as lipid sensors include the oxysterol receptors (LXRα and β), the bile acid receptor (FXR), and the vitamin D receptor (VDR). Elucidation of the ligands and physiologic functions of these receptors has led to the identification of a lipid metabolic cascade that is initiated by the lipid ligands binding to their cognate nuclear receptor. Upon ligand binding, the receptor activates expression of 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, these lipid-sensing receptors maintain homeostatic levels of dietary lipids. The finding that this class of receptors function as key regulators of cholesterol and bile acid homeostasis has had important therapeutic implications for the potential discovery of drugs targeted against these receptors.
More recently, we have extended the search for orphan receptor ligands to invertebrates by discovering the endogenous hormonal ligands for the C. elegans nuclear receptor, DAF-12. This receptor regulates reproduction and longevity in the nematode worm, and the identification of its ligands as being steroid hormones-like hormones represents the first demonstration of such hormones in invertebrates. Furthermore, this work has revealed that endocrine regulation of reproduction is a paradigm that is conserved from worms to humans.
RESEARCH INTERESTS
Molecular Biology of Orphan Nuclear Receptors
The Role of Nuclear Receptors in Lipid Metabolism
Transcription Factors and Gene Expression
RECENT PUBLICATIONS
Antonio Moschetta, Angie L. Bookout, and David J. Mangelsdorf, "Prevention of Cholesterol Gallstone Disease by FXR Agonists in a Mouse Model" Nature Medicine, 10:1352-1358, December 2004
Motola, D.L., Cummins, C.L., Rottiers, V., Sharma, K.K., Li, T., Li, Y., Suino-Powell, K., Xu, H.E., Auchus, R.J., Antebi, A., Mangelsdorf, D.J., "Identification of ligands for DAF-12 that govern dauer formation and reproduction in C. elegans." Cell, 124:1209-1223, 2006
Bookout, A.L., Jeong, Y., Downes, M., Yu, R.T., Evans, R.M., Mangelsdorf, D.M., "Anatomical profiling of nuclear receptor expression reveals a hierarchical transcriptional network." Cell, 126:789-799, 2006
Inagaki, T., Dutchak, P., Zhao, G., Ding, X., Gautron, L., Parameswara, V., Li, Y., Goetz, R., Mohammadi, M., Esser, V., Elmquist, J.K., Gerard, R.D., Burgess, S.C., Hammer, R.E., Mangelsdorf, D.J., Kliewer, S.A., "Endocrine Regulation of the Fasting Response by PPARalpha-mediated Induction of Fibroblast Growth Factor 21." Cell Metabolism, 5:415-425, 2007
SIGNIFICANT PUBLICATIONS
Janowski, B.A., Willy, P.J., Rama Devi, T., Falck, J.R., and Mangelsdorf, D.J., "Identification of an oxysterol signaling pathway mediated by the nuclear receptor, LXR-alpha" Nature, 383:728-731, 1996
Peet, D.J., Turley, S.D., Ma, W., Janowski, B.A., Lobaccaro, J.A., Hammer, R.E., and Mangelsdorf, D.J., "Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor, LXRα." Cell, 93:693-704, May 1998
Makishima, M., Okamoto, A.Y., Repa, J.J., Tu, H., Learned, R.M., Luk, A., Hull, M.V., Lustig, K.D., Mangelsdorf, D.J., and Shan, B., "Identification of a nuclear receptor for bile acids." Science, 284:362-365, 1999
Repa, J.J., Turley, S.D., Lobaccaro, J.A., Medina, J., Li, L., Lustig, K., Shan , B., Heyman, R.A., Dietschy, J.M., and Mangelsdorf, D.J., "Regulation of absorption and ABC1-mediated efflux of cholesterol by RXR heterodimers" Science, 289:1524-1529, 2000
Inagaki, T., Dutchak, P., Zhao, G., Ding, X., Gautron, L., Parameswara, V., Li, Y., Goetz, R., Mohammadi, M., Esser, V., Elmquist, J.K., Gerard, R.D., Burgess, S.C., Hammer, R.E., Mangelsdorf, D.J., Kliewer, S.A., "Endocrine Regulation of the Fasting Response by PPARalpha-mediated Induction of Fibroblast Growth Factor 21." Cell Metabolism, 5:415-425, 2007
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