Research Project 2
Project Narative
This project is directed at characterizing the molecular and genetic bases of liver damage caused by toxicant exposure. The project will also evaluate the efficacy of pharmacological agents in minimizing the damage induced by toxicant exposure in both preventive and intervention preclinical settings, and will thereby aid in the development of new diagnostics and therapeutics for combating toxicant exposure.
Summary of Project
Superfund site toxicants pose a significant hazard to human health, in part through their ability to alter patterns of gene expression. One of the most prevalent diseases, toxicant-associated steatohepatitis (TASH), is phenotypically similar to nonalcoholic steatohepatitis (NASH) without the underlying obesity. Building on this similarity, this project will provide mechanistic insight into TASH-induced liver damage and models of exposure. With a focus on the epigenetic and immune responses, the overall goal of the project is to identify potential intervention or prevention therapies and/or therapeutic targets. In Aim 1 we will explore the role of regulatory enhancers, key genomic mediators of tissue fibrosis, in mouse models of TASH by mapping injury-induced epigenetic changes in stellate cells, hepatocytes, and immune cells. In parallel studies, the therapeutic efficacy of epigenetically-targeted small molecule modulators will be determined in both intervention and prevention models of TASH. In Aim 2 we will profile the immune response to toxicant-induced liver damage in mice during the initial injury, damage/repair, and resolution stages. Based on these findings, potential immune-targeted therapies for the treatment TAFLD and TASH will be explored. In Aim 3, the epigenetic and immunological consequences of chronic toxicant exposure will be explored in a novel genetic mouse model of TAFLD (SMRTRID mice). In summary, this project will provide valuable insight on the molecular mechanisms underlying TAFLD and TASH as well as a roadmap for potential new therapies.
Publications
Evans RM, Wei Z. Interorgan crosstalk in pancreatic islet function and pathology. FEBS Lett. 2022 Jan 11. doi:10.1002/1873-3468.14282. Epub ahead of print. PMID: 35014695.
Sancar G, Liu S, Gasser E, Alvarez JG, Moutos C, Kim K, van Zutphen T, Wang Y, Huddy TF, Ross B, Dai Y, Zepeda D, Collins B, Tilley E, Kolar MJ, Yu RT, Atkins AR, van Dijk TH, Saghatelian A, Jonker JW, Downes M, Evans RM. FGF1 and insulin control lipolysis by convergent pathways. Cell Metab. 2022 Jan 4;34(1):171-183.e6. doi:10.1016/j.cmet.2021.12.004. PMID: 34986332; PMCID: PMC8863067.
Iwamoto M, Masuya T, Hosose M, Tagawa K, Ishibashi T, Suyama K, Nose T, Yoshihara E, Downes M, Evans RM, Matsushima A. Bisphenol A derivatives act as novel coactivator-binding inhibitors for estrogen receptor β. J Biol Chem. 2021 Nov;297(5):101173. doi:10.1016/j.jbc.2021.101173. Epub 2021 Sep 6. PMID: 34499926; PMCID: PMC8551653.
Wang L, Oh TG, Magida J, Estepa G, Obayomi SMB, Chong LW, Gatchalian J, Yu RT, Atkins AR, Hargreaves D, Downes M, Wei Z, Evans RM. Bromodomain containing 9 (BRD9) regulates macrophage inflammatory responses by potentiating glucocorticoid receptor activity. Proc Natl Acad Sci U S A. 2021 Aug 31;118(35):e2109517118. doi:10.1073/pnas.2109517118. PMID: 34446564; PMCID: PMC8536317.
Tang Q, Evans RM. Colon cancer checks in when bile acids check out: the bile acid-nuclear receptor axis in colon cancer. Essays Biochem. 2021 Dec 17;65(6):1015-1024. doi:10.1042/EBC20210038. PMID: 34414429; PMCID: PMC8628182.
Abu-Odeh M, Zhang Y, Reilly SM, Ebadat N, Keinan O, Valentine JM, Hafezi-Bakhtiari M, Ashayer H, Mamoun L, Zhou X, Zhang J, Yu RT, Dai Y, Liddle C, Downes M, Evans RM, Kliewer SA, Mangelsdorf DJ, Saltiel AR. FGF21 promotes thermogenic gene expression as an autocrine factor in adipocytes. Cell Rep. 2021 Jun 29;35(13):109331. doi:10.1016/j.celrep.2021.109331. PMID: 34192547; PMCID: PMC8293281.
Xu S, Chaudhary O, Rodríguez-Morales P, Sun X, Chen D, Zappasodi R, Xu Z, Pinto AFM, Williams A, Schulze I, Farsakoglu Y, Varanasi SK, Low JS, Tang W, Wang H, McDonald B, Tripple V, Downes M, Evans RM, Abumrad NA, Merghoub T, Wolchok JD, Shokhirev MN, Ho PC, Witztum JL, Emu B, Cui G, Kaech SM. Uptake of oxidized lipids by the scavenger receptor CD36 promotes lipid peroxidation and dysfunction in CD8+ T cells in tumors. Immunity. 2021 Jul 13;54(7):1561-1577.e7. doi:10.1016/j.immuni.2021.05.003. Epub 2021 Jun 7. PMID: 34102100
Zhou R, Llorente C, Cao J, Zaramela LS, Zeng S, Gao B, Li SZ, Welch RD, Huang FQ, Qi LW, Pan C, Huang Y, Zhou P, Beussen I, Zhang Y, Bryam G, Fiehn O, Wang L, Liu EH, Yu RT, Downes M, Evans RM, Goglin K, Fouts DE, Brenner DA, Bode L, Fan X, Zengler K, Schnabl B. Intestinal α1-2-Fucosylation Contributes to Obesity and Steatohepatitis in Mice. Cell Mol Gastroenterol Hepatol. 2021;12(1):293-320. doi: 10.1016/j.jcmgh.2021.02.009. Epub 2021 Feb 22. PMID: 33631374; PMCID: PMC8166943.
Quinn R.A., Melnik A.V., Vrbanac A., Fu T., Patras K.A., Christy M.P., Bodai Z., Belda-Ferre P., Tripathi A., Chung L.K., Downes M., Welch R.D., Quinn M., Humphrey G., Panitchpakdi M., Weldon K.C., Aksenov A., da Silva R., Avila-Pacheco J., Clish C., Bae S., Mallick H., Franzosa E.A., Lloyd-Price J., Bussell R., Thron T., Nelson A.T., Wang M., Leszczynski E., Vargas F., Gauglitz J.M., Meehan M.J., Gentry E., Arthur T.D., Komor A.C., Poulsen O., Boland B.S., Chang J.T., Sandborn W.J., Lim M., Garg N., Lumeng J.C., Xavier R.J., Kazmierczak B.I., Jain R., Egan M., Rhee K.E., Ferguson D., Raffatellu M., Vlamakis H., Haddad G.G., Siegel D., Huttenhower C., Mazmanian S.K., Evans R.M., Nizet V., Knight R., Dorrestein P.C. (2020) Global chemical effects of the microbiome include new bile-acid conjugations. Nature 579, 123–129. doi: 10.1038/s41586-020-2047-9
Sun, X., Seidman, J.S., Zhao, P., Troutman, T.D., Spann, N.J., Que, X., Zhou, F., Liao, Z., Pasillas, M., Yang, X., Magida, J.A., Kisseleva, T., Brenner, D.A.,Downes, M., Evans, R.M., Saltiel, A.R., Tsimikas, S., Glass, C.K., Witztum, J.L. (2020) Neutralization of Oxidized Phospholipids Ameliorates Non-alcoholic Steatohepatitis. Cell Metab. Jan 7;31(1):189-206.e8.
doi: 10.1016/j.cmet.2019.10.014
Cai, D., Wang, J., Gao, B., Li, J., Wu, F., Zou, J.X., Xu, J., Jiang, Y., Zou, H., Huang, Z., Borowsky, A.D., Bold, R.J., Lara, P.N., Li, J.J., Chen, X., Lam, K.S., To, K.F., Kung, H.J., Fiehn, O., Zhao, R., Evans, R.M., Chen, H.W. (2019) RORy is a targetable master regulator of cholesterol biosynthesis in a cancer subtype. Nat Commun. Oct 11;10(1):4621.
doi: 10.1038/s41467-019-12529-3
Chang, C., Loo, C.S., Zhao, X., Solt, L.A., Liang, Y., Bapat, S.P., Cho, H., Kamenecka, T.M., Leblanc, M., Atkins, A.R., Yu, R.T., Downes, M., Burris, T.P., Evans, R.M., Zheng, Y. (2019) The nuclear receptor REV-ERBα modulates Th17 cell-mediated autoimmune disease. Proc Natl Acad Sci U S A. Sep 10;116(37):18528-18536. doi: 10.1073/pnas.1907563116.
Mouzaki, M., Loomba, R. (2019) Insights into the evolving role of the gut microbiome in nonalcoholic fatty liver disease: rationale and prospects for therapeutic intervention. Therap Adv Gastroenterol. 12:1756284819858470. doi: 10.1177/1756284819858470. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6591661/) eCollection 2019. Review.
Fu, T., Coulter, S., Yoshihara, E., Oh, T.G., Fang, S., Cayabyab, F., Zhu, Q., Zhang, T., Leblanc, M., Liu, S., He, M., Waizenegger, W., Gasser, E., Schnabl, B., Atkins, A.R., Yu, R.T., Knight, R., Liddle, C., Downes, M., Evans, R.M. (2019) FXR Regulates Intestinal Cancer Stem Cell Proliferation. Cell. 176(5):1098-1112.e18. doi: 10.1016/j.cell.2019.01.036.
Wei, Z., Yoshihara, E., He, N., Hah, N., Fan, W., Pinto, A.F.M., Huddy, T., Wang, Y., Ross, B., Estepa, G., Dai, Y., Ding, N., Sherman, M.H., Fang, S., Zhao, X., Liddle, C., Atkins, A.R., Yu, R.T., Downes, M., Evans, R.M. (2018) Vitamin D Switches BAF Complexes to Protect β Cells. Cell. 173(5):1135-1149.e15. doi: 10.1016/j.cell.2018.04.013. Epub 2018 May 10.
Ahmadian, M., Liu, S., Reilly, S.M., Hah, N., Fan, W., Yoshihara, E., Jha, P., De Magalhaes Filho, C.D., Jacinto, S., Gomez, A.V., Dai, Y., Yu, R.T., Liddle, C., Atkins, A.R., Auwerx, J., Saltiel, A.R., Downes, M., Evans, R.M. (2018) ERRγ Preserves Brown Fat Innate Thermogenic Activity. Cell Rep. 22(11):2849-2859. doi: 10.1016/j.celrep.2018.02.061.
Fan, W., He, N., Lin, C.S., Wei Z., Hah, N., Waizenegger, W., He, M.X., Liddle, C., Yu, R.T., Atkins, A.R., Downes, M., Evans, R.M. (2018) ERRγ Promotes Angiogenesis, Mitochondrial Biogenesis, and Oxidative Remodeling in PGC1α/β-Deficient Muscle. Cell Rep. 22(10):2521-2529. doi: 10.1016/j.celrep.2018.02.047.
Dickey A.S., Sanchez D.N., Arreola M., Sampat K.R., Fan W., Arbez N., Akimov S., Van Kanegan M.J., Ohnishi K., Gilmore-Hall S.K., Flores A.L., Nguyen J.M., Lomas N., Hsu C.L., Lo D.C., Ross C.A., Masliah E., Evans R.M., La Spada A.R. PPARδ activation by bexarotene promotes neuroprotection by restoring bioenergetic and quality control homeostasis. (2017) Sci Transl Med. 9(419). pii: eaal2332. doi: 10.1126/scitranslmed.aal2332.
Hartmann P., Hochrath K., Horvath A., Chen P., Seebauer C.T., Llorente C., Wang L., Alnouti Y., Fouts D.E., Stärkel P., Loomba R., Coulter S., Liddle C., Yu R.T., Ling L., Rossi S.J., DePaoli A.M., Downes M., Evans R.M., Brenner D.A., Schnabl B. (2017) Modulation of the intestinal bile acid-FXR-FGF15 axis improves alcoholic liver disease in mice. Hepatology. doi: 10.1002/hep.29676.
Shalapour, S., Lin, X.J., Bastian, I.N., Brain, J., Burt, A.D., Aksenov, A.A., Vrbanac, A.F., Li, W., Perkins, A., Matsutani, T., Zhong, Z., Dhar, D., Navas-Molina, J.A., Xu, J., Loomba, R., Downes, M., Yu, R.T., Evans, R.M., Dorrestein, P.C., Knight, R., Benner, C., Anstee, Q.M., Karin, M. (2017). Inflammation-induced IgA+ cells dismantle anti-liver cancer immunity. Nature. 551, 340-345. doi: 10.1038/nature24302.
Cao Q., Zhao X., Bai J., Gery S., Sun H., Lin D.C., Chen Q., Chen Z., Mack L., Yang H., Deng R., Shi X., Chong L.W., Cho H., Xie J., Li Q.Z., Müschen M., Atkins A.R., Liddle C., Yu R.T., Alkan S., Said J.W., Zheng Y., Downes M., Evans R.M., Koeffler H.P. (2017) Circadian clock cryptochrome proteins regulate autoimmunity. Proc Natl Acad Sci U S A. 114(47):12548-12553. doi: 10.1073/pnas.1619119114.
He N., Fan W., Henriquez B., Yu R.T., Atkins A.R., Liddle C., Zheng Y., Downes M., Evans R.M. (2017) Metabolic control of regulatory T cell (Treg) survival and function by Lkb1. Proc Natl Acad Sci U S A. 114(47):12542-12547. doi: 10.1073/pnas.1715363114.
Wang J., He N., Zhang N., Quan D., Zhang S., Zhang C., Yu R.T., Atkins A.R., Zhu R., Yang C., Cui Y., Liddle C., Downes M., Xiao H., Zheng Y., Auwerx J., Evans R.M., Leng Q. (2017) NCoR1 restrains thymic negative selection by repressing Bim expression to spare thymocytes undergoing positive selection. Nat Commun. 8(1):959. doi: 10.1038/s41467-017-00931-8.
Fan W., Waizenegger W., Lin C.S., Sorrentino V., He M.X., Wall C.E., Li H., Liddle C., Yu R.T., Atkins A.R., Auwerx J., Downes M., Evans R.M. (2017) PPARδ Promotes Running Endurance by Preserving Glucose. Cell Metab. 25(5):1186-1193.e4. doi: 10.1016/j.cmet.2017.04.006.
Doktorova M., Zwarts I., Zutphen T.V., Dijk T.H., Bloks V.W., Harkema L., Bruin A., Downes M., Evans R.M., Verkade H.J., Jonker J.W. (2017) Intestinal PPARδ protects against diet-induced obesity, insulin resistance and dyslipidemia. Sci Rep. 7(1):846. doi: 10.1038/s41598-017-00889-z.
Wu C.C., Baiga T.J., Downes M., La Clair J.J., Atkins A.R., Richard S.B., Fan W., Stockley-Noel T.A., Bowman M.E., Noel J.P., Evans R.M. (2017) Structural basis for specific ligation of the peroxisome proliferator-activated receptor δ. 114(13):E2563-E2570. doi: 10.1073/pnas.1621513114.
De Magalhaes Filho C.D., Downes M., Evans R.M. (2017) Farnesoid X Receptor an Emerging Target to Combat Obesity. Dig Dis. 35(3):185-190. doi: 10.1159/000450909.
Chen, S., Lu, W., Yueh, M.-F., Rettenmeier, E., Liu, M., Auwerx, J., Yu, R.T., Evans, R.M., Wang, K., Karin, M., Tukey, R.H. (2017) Intestinal NCoR1, a newly discovered regulator of epithelial cell maturation, controls neonatal hyperbilirubinemia. Proc. Nat. Acad. Sci. USA.114:E1432-E1440. doi: 10.1073/pnas.1700232114.
Sherman M.H., Yu R.T., Tseng T.W., Sousa C.M., Liu S., Truitt M.L., He N., Ding N., Liddle C., Atkins A.R., Lebland M., Collisson E.A., Asara J.M., Kimmelman A.C., Downes M., Evans R.M. (2017) Stromal cues regulate the pancreatic cancer epigenome and metabolome. Proc Natl Acad Sci U S A. 114: 1129-1134. doi: 10.1073/pnas.1620164114.
Chung H.K., Ryu D., Kim K.S., Chang J.Y., Kim Y.K., Yi H.-S., Kang S.G., Choi M.J., Lee S.E., Jung S.B., Ryu M.J., Kim S.J., Kweon G.R., Kim H., Hwang J.H., Lee C.-H., Lee S.-J., Wall C.E., Downes M., Evans R.M., Auwerx J., Shong M. (2017) Growth differentiation factor 15 (GDF15) is a myomitokine governing systemic energy homeostasis. J Cell Biol. 216: 149-165. doi: 10.1083/jcb.201607110.
Fan W., Evans R.M.. (2017) Exercise Mimetics: Impact on Health and Performance. Cell Metab. 25:(2)242-247. doi: 10.1016/j.cmet.2016.10.022.
Wall C.E., Yu R.T., Atkins A.R., Downes M., Evans R.M. (2016) Nuclear receptors and AMPK: can exercise mimetics cure diabetes?J Mol Endocrinol. 2016 Apr 22. pii: JME-16-0073. doi: 10.1530/JME-16-0073.
Yoshihara E., Wei Z., Lin C.S., Fang S., Ahmadian M., Kida Y., Tseng T., Dai Y., Yu R.T., Liddle C., Atkins A.R., Downes M., Evans R.M. (2016) ERRγ Is Required for the Metabolic Maturation of Therapeutically Functional Glucose-Responsive β Cells.Cell Metab. 23:622-34. doi: 10.1016/j.cmet.2016.03.005.
Booth D., Ding N., Parnell G., Shahijanian F., Coulter S., Schibeci S., Atkins A., Stewart G., Evans R.M., Downes M., Liddle C. (2016) Cistromic and genetic Evidence that the Vitamin D Receptor mediates Susceptibility to latitude-dependent Autoimmune Diseases.17:213-9. doi: 10.1038/gene.2016.12.
Liu, W., Struik, D., Nies, V. J., Jurdzinski, A., Harkema, L., de Bruin, A., Verkade, H. J., Downes, M., Evans, R. M., van Zutphen, T., Jonker, J. W. (2016) Effective treatment of steatosis and steatohepatitis by fibroblast growth factor 1 in mouse models of nonalcoholic fatty liver disease. Proc Natl Acad Sci U S A. 113(8):2288-93. doi: 10.1073/pnas.1525093113. Epub 2016 Feb 8.
Ding, N., Hah, N., Yu, R. T., Sherman, M. H., Benner, C., Leblanc, M., He, M., Liddle, C., Downes, M., Evans, R. M. (2015) BRD4 is a novel therapeutic target for liver fibrosis. Proc Natl Acad Sci U S A.112(51):15713-8. doi: 10.1073/pnas.1522163112.
Bapat, S. P., Myoung Suh, J., Fang, S., Liu, S., Zhang, Y., Cheng, A., Zhou, C., Liang, Y., LeBlanc, M., Liddle, C., Atkins, A. R., Yu, R. T., Downes, M., Evans, R. M., Zheng, Y. (2015) Depletion of fat-resident Treg cells prevents age-associated insulin resistance. Nature. 528(7580):137-41. doi: 10.1038/nature16151.
Ranjit, S., Dvornikov, A., Stakic, M., Hong, S. H., Levi, M., Evans, R. M., Gratton, E. (2015) Imaging Fibrosis and Separating Collagens using Second Harmonic Generation and Phasor Approach to Fluorescence Lifetime Imaging. Sci Rep. 5:13378. doi: 10.1038/srep13378.
Arensman, M. D., Nguyen, P., Kershaw, K. M., Lay, A. R., Ostertag-Hill, C. A., Sherman, M. H., Downes, M., Liddle, C., Evans, R. M., Dawson, D. W. (2015) Calcipotriol Targets LRP6 to Inhibit Wnt Signaling in Pancreatic Cancer. Mol Cancer Res. 13(11):1509-19. doi: 10.1158/1541-7786.MCR-15-0204.
Suh, J.M., Jonker, J. W., Ahmadian, M., Goetz, R., Lackey, D., Osborn, O., Huang, Z., Liu, W., Yoshihara, E., van Dijk, T. H., Havinga, R., Fan, W., Yin, Y. Q., Yu, R. T., Liddle, C., Atkins, A. R., Olefsky, J. M., Mohammadi, M., Downes, M., Evans, R. M. (2014) Corrigendum: Endocrinization of FGF1 produces a neomorphic and potent insulin sensitizer. Nature. 520(7547):388. doi: 10.1038/nature14304.
Hah, N., Benner, C., Chong, L. W., Yu, R. T., Downes, M., Evans, R. M. (2015) Inflammation-sensitive super enhancers form domains of coordinately regulated enhancer RNAs. Proc Natl Acad Sci U S A. 112(3). E297-302.
Fang, S., Suh, J. M., Reilly, S. M., Yu, E., Osborn, O., Lackey, D., Yoshihara, E., Perino, A., Jacinto, S., Lukasheva, Y., Atkins, A. R., Khvat, A., Schnabl, B., Yu, R. T., Brenner, D. A., Coulter, S., Liddle, C., Schoonjans, K., Olefsky, J. M., Saltiel, A. R., Downes, M., Evans, R. M. (2015) Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nat Med. 21(2):159-65. doi: 10.1038/nm.3760.
Fan, W., Evans, R. (2014) PPARs and ERRs: molecular mediators of mitochondrial metabolism. Curr Opin Cell Biol. 33:49-54. doi: 10.1016/j.ceb.2014.11.002.
Yueh, M. F., Taniguchi, K., Chen, S., Evans, R. M., Hammock, B. D., Karin, M., Tukey, R. H. (2014) The commonly used antimicrobial additive triclosan is a liver tumor promoter. Proc Natl Acad Sci USA. 111(48):17200-5. doi: 10.1073/pnas.1419119111.
Sherman, M. H., Yu, R. T., Engle, D. D., Ding, N., Atkins, A. R., Tiriac, H., Collisson, E. A., Connor, F., Van Dyke, T., Kozlov, S., Martin, P., Tseng, T. W., Dawson, D. W., Donahue, T. R., Masamune, A., Shimosegawa, T., Apte, M. V., Wilson, J. S., Ng, B., Lau, S. L., Gunton, J. E., Wahl, G. M., Hunter, T., Drebin, J. A., O'Dwyer, P. J., Liddle, C., Tuveson, D. A., Downes, M., Evans, R. M. (2014) Vitamin d receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy. Cell. 159(1):80-93. doi: 10.1016/j.cell.2014.08.007.
Suh, J. M., Jonker, J. W., Ahmadian, M., Goetz, R., Lackey, D., Osborn, O., Huang, Z., Liu, W., Yoshihara, E., van Dijk, T. H., Havinga, R., Fan, W., Yin, Y. Q., Yu, R. T., Liddle, C., Atkins, A. R., Olefsky, J. M., Mohammadi, M., Downes, M., Evans, R. M. (2014) Endocrinization of FGF1 produces a neomorphic and potent insulin sensitizer. Nature. doi: 10.1038/nature13540.
Zhao, X., Cho, H., Yu, R. T., Atkins, A. R., Downes, M., Evans, R. M. (2014) Nuclear receptors rock around the clock. EMBO Rep. 15(5):518-28. doi: 10.1002/embr.201338271.
Evans, R. M., Mangelsdorf, D. J. (2014) Nuclear Receptors, RXR, and the Big Bang. Cell. 157(1):255-66. doi: 10.1016/j.cell.2014.03.012.
Hong, S. H., Ahmadian, M., Yu, R. T., Atkins, A. R., Downes, M., Evans, R. M. (2014) Nuclear receptors and metabolism: from feast to famine. Diabetologia. 57(5):860-7. doi: 10.1007/s00125-014-3209-9.
d'Uscio, L. V., He, T., Santhanam, A. V., Tai, L. J., Evans, R. M., Katusic, Z. S. (2014) Mechanisms of vascular dysfunction in mice with endothelium-specific deletion of the PPAR-δ gene. Am J Physiol Heart Circ Physiol. 306(7):H1001-10. doi: 10.1152/ajpheart.00761.2013.
Fan, W., Atkins, A. R., Yu, R. T., Downes, M., Evans, R. M. (2013) Road to exercise mimetics: targeting nuclear receptors in skeletal muscle. J Mol Endocrinol. 51(3):T87-T100. doi: 10.1530/JME-13-0258.
Ding, N., Liddle, C., Evans, R. M., Downes, M. (2013) Hepatic actions of vitamin D receptor ligands: a sunshine option for chronic liver disease? Expert Rev Clin Pharmacol. 6(6):597-9. doi: 10.1586/17512433.2013.841078.
Kittayaruksakul, S., Zhao, W., Xu, M., Ren, S., Lu, J., Wang, J., Downes, M., Evans, R. M., Venkataramanan R, Chatsudthipong V, Xie W. (2013) Identification of three novel natural product compounds that activate PXR and CAR and inhibit inflammation. Pharm Res. 30(9):2199-208. doi: 10.1007/s11095-013-1101-9.
Du, L., Bergsneider, M., Mirsadraei, L., Young, S. H., Jonker, J. W., Downes, M., Yong, W. H., Evans, R. M., Heaney, A. P. (2013) Evidence for orphan nuclear receptor TR4 in the etiology of Cushing disease. Proc Natl Acad Sci USA. 110(21):8555-60. doi: 10.1073/pnas.1306182110.
Ahmadian, M., Suh, J. M., Hah, N., Liddle, C., Atkins, A. R., Downes, M., Evans, R. M. (2013) PPARγ signaling and metabolism: the good, the bad and the future. Nat Med. 19(5):557-66. doi: 10.1038/nm.3159.
Ding, N., Yu, R. T., Subramaniam, N., Sherman, M. H., Wilson, C., Rao, R., Leblanc, M., Coulter, S., He, M., Scott, C., Lau, S. L., Atkins, A. R., Barish, G. D., Gunton, J. E., Liddle, C., Downes, M., Evans, R. M. (2013) A vitamin D receptor/SMAD genomic circuit gates hepatic fibrotic response. Cell. 153(3):601-13. doi: 10.1016/j.cell.2013.03.028.
Uhlenhaut, N. H., Barish, G. D., Yu, R. T., Downes, M., Karunasiri, M., Liddle, C., Schwalie, P., Hübner, N., Evans, R. M. (2013) Insights into negative regulation by the glucocorticoid receptor from genome-wide profiling of inflammatory cistromes. Mol Cell. 49(1):158-71. doi: 10.1016/j.molcel.2012.10.013.
Li, T., Yu, R. T., Atkins, A. R., Downes, M., Tukey, R. H., Evans, R. M. (2012) Targeting the pregnane X receptor in liver injury. Expert Opin Ther Targets. 16(11):1075-83. doi: 10.1517/14728222.2012.715634.
Yueh, M. F., Li, T., Evans, R. M., Hammock, B., Tukey, R. H. (2012) Triclocarban mediates induction of xenobiotic metabolism through activation of the constitutive androstane receptor and the estrogen receptor alpha. PLoS One. 7(6):e37705. doi: 10.1371/journal.pone.0037705.
Fan, W., Downes, M., Atkins, A., Yu, R., Evans, R. M. (2011) Nuclear receptors and AMPK: resetting metabolism. Cold Spring Harb Symp Quant Biol. 76:17-22. doi: 10.1101/sqb.2012.76.010470.
Chen, S., Yueh, M. F., Evans, R. M., Tukey, R. H. (2012) Pregnane-x-receptor controls hepatic glucuronidation during pregnancy and neonatal development in humanized UGT1 mice. Hepatology. 56(2):658-67. doi: 10.1002/hep.25671.
Noreault-Conti, T. L., Fellows, A., Jacobs, J. M., Trask, H. W., Strom, S. C., Evans, R. M., Wrighton, S. A., Sinclair, P. R., Sinclair, J. F., Nichols, R. C. (2012) Arsenic decreases RXRα-dependent transcription of CYP3A and suppresses immune regulators in hepatocytes. Int Immunopharmacol. 12(4):651-6. doi: 10.1016/j.intimp.2012.01.008.
Kacevska, M., Downes, M. R., Sharma, R., Evans, R. M., Clarke, S. J., Liddle, C., Robertson, G. R. (2011) Extrahepatic cancer suppresses nuclear receptor-regulated drug metabolism. Clin Cancer Res. 17(10):3170-80. doi: 10.1158/1078-0432.CCR-10-3289.
Lamia, K. A., Evans, R. M. (2010) Metabolism: Tick, tock, a beta-cell clock. Nature. 466(7306):571-2. doi: 10.1038/466571a.
Sonoda, J., Mehl, I. R., Chong, L. W., Nofsinger, R. R., Evans, R. M. (2007) PGC-1beta controls mitochondrial metabolism to modulate circadian activity, adaptive thermogenesis, and hepatic steatosis. Proc Natl Acad Sci USA. 104(12):5223-8. doi: 10.1073/pnas.0611623104.
Germain, P., Chambon, P., Eichele, G., Evans, R. M., Lazar, M. A., Leid, M., De Lera, A. R., Lotan, R., Mangelsdorf, D. J., Gronemeyer, H. (2006) Pharmacol Rev. 58(4), 760-72.
Germain, P., Chambon, P., Eichele, G., Evans, R. M., Lazar, M. A., Leid, M., De Lera, A. R., Lotan, R., Mangelsdorf, D. J., Gronemeyer H. (2006) International Union of Pharmacology. LX. Retinoic acid receptors. Pharmacol Rev. 58(4), 712-25. doi: 10.1124/pr.58.4.4
Stedman, C., Liddle, C., Coulter, S., Sonoda, J., Alvarez, J. G., Evans, R. M., and Downes, M. (2006) Benefit of FXR inhibition in obstructive cholestasis. Proc Natl Acad Sci USA. 103(30):11323-8. doi: 10.1073/pnas.0604772103
Main Contact Information
The Salk Institute of Biological Studies
Gene Expression Laboratory
10010 North Torrey Pines Road
La Jolla, CA 92037
Project Leaders
- Dr. Ronald M. Evans, March of Dimes Chair in Molecular and Developmental Biology, SALK Institute for Biological Studies
- Dr. Michael Downes, Senior Project Scientist, SALK Institute for Biological Studies
Superfund Project Members
- Christi Brondos, Administrator
- Lita Ong, Lab Manager
- Benson Lu, Post-Doctoral Scholar
- Tae Gyu Oh, Post-Doctoral Scholar
- Ruth Yu, Staff Researcher
Contact
UCSD Superfund Research Center
University of California, San Diego
Pharmacology Department
9500 Gilman Drive, Mail Code 0722
La Jolla, CA 92093-0722
Supporting Partners
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