Biography Dr. David J. Mangelsdorf received his BS in Biology and Chemistry from Northern Arizona University in Flagstaff (1981) and his PhD in Biochemistry from the University of Arizona in Tucson (1987). He did his postdoctoral studies at The Salk Institute for Biological Studies. Since 1993 he has been at UT Southwestern, where he currently is Professor and Chair of the Department of Pharmacology, and an Investigator of the Howard Hughes Medical Institute. He holds the Raymond and Ellen Willie Distinguished Chair in Molecular Neuropharmacology, in Honor of Harold B. Crasilneck, PhD and the Distinguished Chair in Pharmacology, and he is a member of the National Academy of Sciences. Dr. Mangelsdorf’s research interests are focused on the mechanism of action of orphan nuclear receptors. Stemming from his early work with Ronald Evans at the Salk Institute and the discovery of RXR and its ligand (9-cis retinoic acid), his lab has since characterized ligands and physiologic functions for the LXRs, which bind oxysterols; FXR, which binds bile acids; and PPARs, which bind fatty acids. Together, these receptors govern nutrient metabolism during feeding and fasting, and they have become therapeutic targets for diseases such as atherosclerosis, cholestasis, and type 2 diabetes. Since 2003, Mangelsdorf has been working jointly with Dr. Steven Kliewer at UT Southwestern. The focus of their work has centered on two new nuclear receptor-initiated endocrine signaling pathways that govern feeding and fasting responses and are mediated by the fibroblast growth factors FGF19 and FGF21. Recently, their lab has also discovered the existence of an orthologous nuclear receptor pathway that is conserved in parasitic nematodes, and has shown that pharmacophores that target this pathway may represent a new class of vermicides. Education Undergraduate Northern Arizona University , Aquatic Biology Graduate School University of Arizona (1987) Honors & Awards The Rolf Luft Award Karolinska Institutet, for outstanding contributions in endocrinology and diabetes research. (2012) National Academy of Sciences (2008) Edith and Peter O’Donnell Award in Medicine The Academy of Medicine, Engineering and Science of Texas (2007) Transatlantic Medal The European Society of Endocrinology (2006) Gerald D. Aurbach Award The Endocrine Society (2004) Heinrich Wieland Prize Boehringer Ingelheim (2003) Adolf Windaus Prize Work in the field of bile acid research (2000) John J. Abel Award in Pharmacology American Society for Pharmacology and Experimental Therapeutics (1997)

Research Interest Molecular Biology of Orphan Nuclear Receptors The Role of Nuclear Receptors in Lipid Metabolism Transcription Factors and Gene Expression

Chen, W., Chen, G., Head, D.L., Mangelsdorf, D.J., Russell, D.W. (2007) Enzymatic reduction of oxysterols impairs LXR signaling in cultured cells and the livers of mice. Cell Metabolism 5: 73-79. PMID: 17189208 Uppal, H., Saini, S.P.S., Moschetta, A., Mu, Y., Zhou, J., Gong, H., Zhai, Y., Ren, S., Michalopoulos, G.K., Mangelsdorf, D.J., Xie, W. (2007) Activation of LXRs prevents bile acid toxicity and cholestasis in female mice. Hepatology 45: 422-432. PMID: 17256725 Baker, K.D., Beckstead, R.B., Mangelsdorf, D.J., Thummel, C.S. (2007) Functional interactions between the moses corepressor and DHR78 nuclear receptor regulate growth in Drosophila. Genes Dev. 21: 450-64. PMID: 17322404. PMCID: 1804333 Gerisch, B., Rottiers, V., Li, D., Motola, D.L., Cummins, C.L., Lehrach, H., Mangelsdorf, D.J., Antebi, A. (2007) A bile acid-like steroid modulates Caenorhabditis elegans lifespan through nuclear receptor signaling. Proc. Natl. Acad. Sci. USA 104: 5014-5019. PMID: 17360327. PMCID: 1821127. Wang, Z., Cummins, C.L., Motola, D.L., Mangelsdorf, D.J. (2007) Bile acid-like hormones function as ligands for the nematode orphan nuclear receptor DAF-12 and govern dauer formation, reproduction and lifespan. In: Bile Acids: Biological Actions and Clinical Relevance—Falk Symposium 155, 14: 99-108. 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. (2007) Endocrine regulation of the fasting response by PPARalpha-mediated induction of fibroblast growth factor 21. Cell Metabolism 5: 415-425. PMID: 17550777 Houten, S.M., Volle, D.H., Cummins, C.L., Mangelsdorf, D.J., Auwerx, J. (2007) In vivo imaging of FXR activity reveals the ileum as the primary bile acid signaling tissue. Molec. Endocr. 21: 1312-1323. PMID: 17426284 Umetani, M., Domoto, H., Gormley, A., Yuhanna, I.S., Cummins, C.L., Javitt, N.B., Korach, K.S., Shaul, P.W., Mangelsdorf, D.J. (2007) 27-Hydroxycholesterol is an endogenous SERM that inhibits the cardiovascular effects of estrogen. Nature Medicine 13: 1185-1192. PMID: 17873880 Jung, D., Inagaki, T., Dawson, P.A., Kliewer, S.A., Mangelsdorf, D.J., Moschetta, A.M. (2007) FXR agonists and FGF15 reduce fecal bile acid excretion in a mouse model of bile acid malabsorption. J. Lipid Res. 48: 2693-2700. PMID: 17823457 Katona, B.W, Cummins, C.L., Ferguson, A.D., Li, T., Schmidt, D.R., Mangelsdorf, D.J., and Covey, D.F. (2007) Synthesis, Characterization, and Receptor Interaction Profiles of Enantiomeric Bile Acids. J. Med. Chem. 50: 6048-6058. PMID: 17963371 Lefterov, I., Bookout, A., Wang, Z., Staufenbiel, M., Mangelsdorf, D.J., and Koldamova, R. (2007) Expression profiling in APP23 mouse brain: inhibition of Abeta amyloidosis and inflammation in response to LXR agonist treatment. Molecular Neurodegeneration 2: 20. PMID: 17953774. PMCID: PMC2214725. DuSell, C., Umetani, M., Shaul, P., Mangelsdorf, D.J., McDonnell, D.P. (2008) 27-Hydroxycholesterol is an endogenous Selective Estrogen Receptor Modulator (SERM). Molec. Endocr. 22: 65-77. PMID: 17872378. PMCID: PMC2194632. Lee, YK, Schmidt, D.R., Cummins, C.L., Choi, M., Peng, L., Zhang, Y., Goodwin, B., Hammer, R.E., Mangelsdorf, D.J., Kliewer, S.A. (2008) Liver receptor homolog-1 regulates bile acid homeostasis but is not essential for feedback regulation of bile acid synthesis. Molec. Endocr. 22:1345-1356. PMID: 18323469. PMCID: PMC2409274. Satapati, S., He, T., Inagaki, T., Potthoff, M., Merritt, M.E., Esser, V., Mangelsdorf, D.J., Kliewer, S.A., Browning, J.D., Burgess, S.C. (2008) Partial resistance to PPAR-alpha agonists in Zucker diabetic fatty (ZDF) rats is associated with defective hepatic mitochondrial metabolism. Diabetes 57:2012-2021. PMID: 18469201. PMCID: 2494699. Inagaki, T., Lin, V.Y., Goetz, R., Mohammadi, M., Mangelsdorf, D.J., Kliewer, S.A. (2008) Inhibition of growth hormone signaling by the fasting-induced hormone FGF21. Cell Metabolism 8:77-83. PMID: 18585098. PMCID: PMC2575072. Schmidt, D.R., Mangelsdorf, D.J. (2008) Nuclear Receptors of the enteric tract: guarding the frontier. Nutrition Reviews 66 (Suppl. 2):S88-S97. PMID: 18844851. PMCID: PMC2741173 Wang, H., Zhang, Y., Yehuda-Shnaidman, E., Medvedev, A.V., Kumar, N., Daniel, K.W. Robidoux, J., Czech, M.P., Mangelsdorf, D.J., Collins, S. (2008) Liver X receptor alpha is a transcriptional repressor of the uncoupling protein 1 gene and the brown fat phenotype Mol. Cell. Biol. 28: 2187-2200. PMID: 18195045. PMCID: PMC2268430. Bethke, A., Fielenbach, N., Wang, Z., Mangelsdorf, D.J., Antebi, A. (2009) Nuclear hormone receptor regulation of microRNAs controls developmental progression. Science 324:95-98. PMID: 19342589. PMCID: PMC2757405 Sharma, K.K., Wang, Z., Motola, D.L., Cummins, C.L., Mangelsdorf, D.J., Auchus, R.J. (2009) Synthesis and activity of dafachronic acid ligands for the C. elegans DAF-12 nuclear hormone receptor. Molec. Endocr. 23:640-648. PMID: 19196833. PMCID: PMC2675950

Xie, C., Jeong, Y., Fu, M., Bookout, A.L., Garcia-Barrio, M.T., Sun, T., Kim, B., Xie, Y., Root, S., Zhang, J., Xu, R., Chen, Y.E., Mangelsdorf, D.J. (2009) Expression profiling of nuclear receptors in human and mouse embryonic stem cells. Molec. Endocr. 23:724-733. PMID: 19196830. PMCID: PMC2675959