Nuclear Receptor Mediated Epigenetic and Immune Cell Changes in Liver Fibrosis Resulting From Toxicant Exposure (Biomedical)

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 exposureThis 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.

Publication

PubMed Central ID: 

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.

PubMed Central ID: 

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.

PubMed Central ID: 

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.

PubMed Central ID: 

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.

PubMed Central ID: 

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.

PubMed Central ID: 

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.

PubMed Central ID: 

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.

PubMed Central ID: 

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.

PubMed Central ID: 

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.

PubMed Central ID: 

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.

PubMed Central ID: 

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.

PubMed Central ID: 

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.

PubMed Central ID: 

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.

PubMed Central ID: 

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.

PubMed Central ID: 

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.

PubMed Central ID: 

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.

PubMed Central ID: 

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.

PubMed Central ID: 

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.

PubMed Central ID: 

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.

PubMed Central ID: 

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 Rep5:13378. doi: 10.1038/srep13378.

PubMed Central ID: 

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.

PubMed Central ID: 

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.

PubMed Central ID: 

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.

PubMed Central ID: 

Fan, W., Evans, R. (2014) PPARs and ERRs: molecular mediators of mitochondrial metabolism. Curr Opin Cell Biol33:49-54. doi: 10.1016/j.ceb.2014.11.002.

PubMed Central ID: 

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.

PubMed Central ID: 

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.

PubMed Central ID: 

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.

PubMed Central ID: 

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.

PubMed Central ID: 

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.

PubMed Central ID: 

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.

PubMed Central ID: 

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.

PubMed Central ID: 

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.

PubMed Central ID: 

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.

PubMed Central ID: 

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.

PubMed Central ID: 

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.

PubMed Central ID: 

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.

PubMed Central ID: 

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.

PubMed Central ID: 

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.

PubMed Central ID: 

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 Targets16(11):1075-83. doi: 10.1517/14728222.2012.715634.

PubMed Central ID: 

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 One7(6):e37705. doi: 10.1371/journal.pone.0037705.

PubMed Central ID: 

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.

PubMed Central ID: 

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.

PubMed Central ID: 

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.

PubMed Central ID: 

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.

PubMed Central ID: 

Lamia, K. A., Evans, R. M. (2010) Metabolism: Tick, tock, a beta-cell clock. Nature. 466(7306):571-2. doi: 10.1038/466571a.

PubMed Central ID: 

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

PubMed Central ID: 

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

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