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

Project 2

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

Project Summary/Abstract:

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.

PubMedID: 29212711

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.

PubMedID: 29159825

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.

PubMedID: 29144460
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.

PubMedID: 29109286
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.

PubMedID: 29109251
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.

PubMedID: 29038463
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.

PubMedID: 28467934
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.

PubMedID: 28404991
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.

PubMedID: 28320959
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.

PubMedID: 28249279

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.

PubMedID: 28167773
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.

PubMedID: 28096419
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.

PubMedID: 27986797

Fan W., Evans R.M.. (2017) Exercise Mimetics: Impact on Health and Performance. Cell Metab. 25:242-247. doi: 10.1016/j.cmet.2016.10.022. PMCID: PMC Journal - In Process

 

PubMedID: 27889389
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.

PubMedID: 27106806
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.

PubMedID: 27076077
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.

PubMedID: 26986782

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. pii: 201525093.

PubMedID: 26858440
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.

PubMedID: 26644586

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.  doi: 10.1038/nature16151.

PubMedID: 26580014
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 Rep. 5, 13378.

PubMedID: 26293987

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. pii: molcanres.0204.2015.

PubMedID: 26224368
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.

PubMedID: 25564661

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. doi: 10.1038/nm.3760.

PubMedID: 25559344

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. doi: 10.1038/nature14304.

PubMedID: 25739500

Fan, W., Evans, R. (2014) PPARs and ERRs: molecular mediators of mitochondrial metabolism. Curr Opin Cell Biol. 33C, 49-54.

PubMedID: 25486445
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.

PubMedID: 25404284
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, 80-93.

PubMedID: 25259922
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.

PubMedID: 25043058
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.

PubMedID: 24737872
PubMed Central ID: 

Evans, R. M., Mangelsdorf, D. J. (2014) Nuclear Receptors, RXR, and the Big Bang. Cell. 157(1), 255-66.

PubMedID: 24679540
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.

PubMedID: 24619218
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.

PubMedID: 24486511
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.

PubMedID: 24280961

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.

PubMedID: 24164608
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.

PubMedID: 23896737
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.

PubMedID: 23653479
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.

PubMedID: 23652116
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.

PubMedID: 23622244
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.

PubMedID: 23159735
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, 658-667.

PubMedID: 22371261

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.

PubMedID: 22913318
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 One.  doi: 10.1371/journal.pone.0037705.

PubMedID: 22761658
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.

PubMedID: 22310326
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.

PubMedID: 22411605
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.

PubMedID: 21498392
PubMed Central ID: 

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

PubMedID: 20671699
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), 5223-5228.

PubMedID: 17360356

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.

PubMedID: 17132853

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.

PubMedID: 17132850
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, 11323-8.

PubMedID: 16844773

Main Contact Information

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)

Contact

UCSD Superfund Research Center
University of California, San Diego
Pharmacology Department
9500 Gilman Drive, Mail Code 0722
La Jolla, CA 92093-0722