The nuclear hormone receptors comprise a family of ligand-activated transcription factors that play pivotal roles in both normal physiology and disease processes. The characterization of these receptors, including their ligands and the genes that they regulate, represents an exciting opportunity to characterize novel biological signaling pathways. In the past, my group has linked nuclear receptors to the regulation of fatty acid, cholesterol, and xenobiotic metabolism. We are currently focused on several nuclear receptors that are highly expressed in the liver and intestine including the bile acid receptor FXR, the fatty acid receptor PPAR, and the orphan nuclear receptor LRH-1. We have shown that these nuclear receptors play crucial roles in diverse biological processes including carbohydrate and lipid metabolism, innate immunity, and endoderm differentiation. We have also recently discovered an unexpected relationship between nuclear receptors and a subfamily of endocrine FGFs that regulate metabolism in response to either the fed or fasted state. We are currently investigating the utility of nuclear receptor ligands and FGFs for treating liver and intestine diseases and metabolic disorders.
RESEARCH INTERESTS
Characterization of nuclear receptor signaling pathways
Roles of nuclear receptors in liver and intestine
Transcription factors and gene expression
RECENT PUBLICATIONS
Kurosu H, Choi M, Ogawa Y, Dickson AS, Goetz R, Eliseenkova AV, Mohammadi M, Rosenblatt KP, Kliewer SA, Kuro-o M, "Tissue-specific expression of beta KLOTHO and fibroblast growth factor receptor isoforms determines metabolic activity of FGF19 and FGF21" J. Biol. Chem., [epub ahead of print] July 2007
Inagaki T, Dutchak P, Zhao G, Ding X, Gautron L, Parameswara V, Li Y, Goetz R, Mohammadi M, Esser V, Elmquist JK, Gerard RD, Burgess SC, Hammer RE, Mangelsdorf DJ, Kliewer SA, "Endocrine Regulation of the Fasting Response by PPARalpha-Mediated Induction of Fibroblast Growth Factor 21" Cell Metab, 5:415-25, June 2007
Choi M, Moschetta A, Bookout AL, Peng L, Umetani M, Holmstrom SR, Suino-Powell K, Xu HE, Richardson JA, Gerard RD, Mangelsdorf DJ, Kliewer SA., "Identification of a hormonal basis for gallbladder filling" Nat Med, 12:1253-5, November 2006
Inagaki T., Moschetta A., Lee Y-K, Peng L., Zhao G., Downes M., Yu R.T., Shelton J.M., Richardson J.A., Repa J.J., Mangelsdorf D.J., Kliewer S.A., "Regulation of antibacterial defense in small intestine by the nuclear bile acid receptor" Proc Natl Acad USA, 103:3920-5, March 2006
Inagaki T., Choi M., Moschetta A., Peng L., Cummins C.L., McDonald J.G., Luo G., Jones S.A., Goodwin B., Richardson J.A., Gerard R.D., Repa J.J., Mangelsdorf D.J., Kliewer S.A., "Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis" Cell Metab, 2:217-225, November 2005
SIGNIFICANT PUBLICATIONS
Kliewer, S.A., Umesono, K., Mangelsdorf, D.J., and Evans, R.M., "Retinoid X receptor interacts with nuclear receptors in retinoic acid, thyroid hormone, and vitamin D3 signalling." Nature, 355:446-449, 1992
Lehmann, J.M., Moore, L.B., Smith-Oliver, T.A., Wilkison, W.O., Willson, T.M., and Kliewer, S.A., "An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma)." J. Biol. Chem, 270:12953-12956, 1995
Kliewer, S.A., Lenhard, J.M., Willson, T.M., Patel, I., Morris, D.C., and Lehmann, J.M., "A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor gamma and promotes adipocyte differentiation." Cell, 83:813-819, 1995
Kliewer, S.A., Lehmann, J.M., and Willson, T.M., "Orphan nuclear receptors: shifting endocrinology into reverse." Science, 284:757-760, 1999
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