Modes-of-action related to repeated dose toxicity: Tissue-specific biological roles of PPAR γ ligand-dependent dysregulation in nonalcoholic fatty liver disease

PPAR Research

Volumn 2014, Issue , 2014, Pages

  Al Sharif, Merilin ^a   Alov, Petko ^a   Vitcheva, Vessela ^a   Pajeva, Ilza ^a   Tsakovska, Ivanka ^a  

^a INSTITUTE OF BIOPHYSICS AND BIOMEDICAL ENGINEERING   (Bulgaria)

Author keywords

[No Author keywords available]

Indexed keywords

ADIPONECTIN; CAVEOLIN 1; CD36 ANTIGEN; FATTY ACID TRANSPORTER; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA LIGAND; RETINOID X RECEPTOR ALPHA; TRANSCRIPTION FACTOR NRF2; TRIACYLGLYCEROL; UNCLASSIFIED DRUG; VERY LOW DENSITY LIPOPROTEIN;

ADIPOCYTE; ADIPOSE TISSUE; ADVERSE OUTCOME; BIOLOGICAL ACTIVITY; CHOLESTEROL SYNTHESIS; CONFORMATIONAL TRANSITION; ENZYME PHOSPHORYLATION; FATTY ACID OXIDATION; FATTY ACID TRANSPORT; FATTY LIVER; GENE EXPRESSION; GENETIC TRANSCRIPTION; HUMAN; INSULIN RESISTANCE; INSULIN SENSITIVITY; LIGAND BINDING; LIPID METABOLISM; LIPID STORAGE; LIPID TRANSPORT; LIPODYSTROPHY; LIPOPROTEIN SECRETION; LIPOTOXICITY; LIVER CELL; LIVER TOXICITY; NONALCOHOLIC FATTY LIVER; NONHUMAN; OXIDATIVE STRESS; REPEATED DRUG DOSE; REVIEW; SUBCUTANEOUS FAT; SUMOYLATION; UPREGULATION; WHITE ADIPOSE TISSUE;

EID: 84897536850     PISSN: 16874757     EISSN: 16874765     Source Type: Journal    
DOI: 10.1155/2014/432647     Document Type: Review

References (72)

1. National Research Council (NRC), Toxicity Testing in the 21st Century: A Vision and A Strategy 2007 Washington, DC, USA National Academies Press
2. ECHA, Guidance on Information Requirements and Chemical Safety Assessment, Chapter R. 7a-Endpoint Specific Guidance 2013 Helsinki, Finland ECHA
3. Prieto P., Testai E., Cronin M., Mahony C., Gocht T., Schwarz M., Current state of the art in repeated dose systemic toxicity testing. Towards the Replacement of In Vivo Repeated Dose Systemic Toxicity TestIng 2011 1 38 46
4. Cronin M. T. D., Richarz A. N., Gocht T., Schwarz M., Mode of action working group: use of mode of action related to repeated dose systemic toxicity-a framework for capturing Information. Towards the Replacement of In Vivo Repeated Dose Systemic Toxicity TestIng 2012 2 284 289
5. OECD, Guidance Document on Developing and Assessing Adverse Outcome Pathways 2013 Paris, France OECD Series on Testing and Assessment No. 184
6. Sass D. A., Chang P., Chopra K. B., Nonalcoholic fatty liver disease: a clinical review. Digestive Diseases and Sciences 2005 50 1 171 180 2-s2.0-14544308375 10.1007/s10620-005-1267-z (Pubitemid 40379159)
7. Landesmann B., Goumenou M., Munn S., Whelan M., Description of prototype modes-of-action related to repeated dose toxicity. Reference Report By the Joint Research Centre of the European Commission 2012 Institute for Health and Consumer Protection
8. Virtue S., Vidal-Puig A., Adipose tissue expandability, lipotoxicity and the metabolic syndrome-an allostatic perspective. Biochimica et Biophysica Acta 2010 1801 3 338 349 2-s2.0-76049099665 10.1016/j.bbalip.2009.12.006
9. Azhar S., Peroxisome proliferator-activated receptors, metabolic syndrome and cardiovascular disease. Future Cardiology 2010 6 5 657 691 2-s2.0-77958060003 10.2217/fca.10.86
10. Fournier T., Tsatsaris V., Handschuh K., Evain-Brion D., PPARs and the placenta. Placenta 2007 28 2-3 65 76 2-s2.0-33845576118 10.1016/j.placenta.2006. 04.009 (Pubitemid 44929358)
11. Costa V., Gallo M. A., Letizia F., Aprile M., Casamassimi A., Ciccodicola A., PPARG: gene expression regulation and next-generation sequencing for unsolved issues. PPAR Research 2010 2010 17 2-s2.0-77957933414 10.1155/2010/409168 409168
12. Luconi M., Cantini G., Serio M., Peroxisome proliferator-activated receptor gamma (PPAR γ): is the genomic activity the only answer? Steroids 2010 75 8-9 585 594 2-s2.0-77954244708 10.1016/j.steroids.2009.10.012
13. Ahmadian M., Suh J. M., Hah N., Liddle C., Atkins A. R., Downes M., Evans R. M., PPAR γ signaling and metabolism: the good, the bad and the future. Nature Medicine 2013 19 5 557 566
14. Chandra V., Huang P., Hamuro Y., Raghuram S., Wang Y., Burris T. P., Rastinejad F., Structure of the intact PPAR- γ -RXR- α nuclear receptor complex on DNA. Nature 2008 456 7220 350 356 2-s2.0-56749130032 10.1038/nature07413
15. Zhu L., Baker S. S., Liu W., Tao M., Patel R., Nowak N. J., Baker R. D., Lipid in the livers of adolescents with nonalcoholic steatohepatitis: combined effects of pathways on steatosis. Metabolism 2011 60 7 1001 1011 2-s2.0-79959336013 10.1016/j.metabol.2010.10.003
16. Lee Y. J., Ko E. H., Kim J. E., Kim E., Lee H., Choi H., Yu J. H., Kim H. J., Seong J. K., Kim K. S., Kim J. W., Nuclear receptor PPAR γ -regulated monoacylglycerol O-acyltransferase 1 (MGAT1) expression is responsible for the lipid accumulation in diet-induced hepatic steatosis. Proceedings of the National Academy of Sciences of the USA 2012 109 34 13656 13661 10.1073/pnas.1203218109
17. Morán-Salvador E., López-Parra M., García-Alonso V., Titos E., Martínez-Clemente M., González-Périz A., López-Vicario C., Barak Y., Arroyo V., Clària J., Role for PPAR γ in obesity-induced hepatic steatosis as determined by hepatocyte- and macrophage-specific conditional knockouts. FASEB Journal 2011 25 8 2538 2550 2-s2.0-80051706346 10.1096/fj.10-173716
18. Satoh H., Ide N., Kagawa Y., Maeda T., Hepatic steatosis with relation to increased expression of peroxisome proliferator-Activated receptor- γ in insulin resistant mice. Biological and Pharmaceutical Bulletin 2013 36 4 616 623 10.1248/bpb.b12-01000
19. Yamazaki T., Shiraishi S., Kishimoto K., Miura S., Ezaki O., An increase in liver PPAR γ 2 is an initial event to induce fatty liver in response to a diet high in butter: PPAR γ 2 knockdown improves fatty liver induced by high-saturated fat. Journal of Nutritional Biochemistry 2011 22 6 543 553 2-s2.0-79955868038 10.1016/j.jnutbio.2010.04.009
20. Sos B. C., Harris C., Nordstrom S. M., Tran J. L., Balázs M., Caplazi P., Febbraio M., Applegate M. A. B., Wagner K., Weiss E. J., Abrogation of growth hormone secretion rescues fatty liver in mice with hepatocyte-specific deletion of JAK2. Journal of Clinical Investigation 2011 121 4 1412 1423 2-s2.0-79960974019
21. Li Y., Dong J., Ding T., Kuo M. S., Cao G., Jiang X. C., Li Z., Sphingomyelin synthase 2 activity and liver steatosis. An effect of ceramide-mediated peroxisome proliferator-activated receptor γ 2 suppression. Arteriosclerosis, Thrombosis, and Vascular Biology 2013 33 7 1513 1520 10.1161/ATVBAHA.113.301498
22. Kumadaki S., Karasawa T., Matsuzaka T., Ema M., Nakagawa Y., Nakakuki M., Saito R., Yahagi N., Iwasaki H., Sone H., Takekoshi K., Yatoh S., Kobayashi K., Takahashi A., Suzuki H., Takahashi S., Yamada N., Shimano H., Inhibition of ubiquitin ligase F-box and WD repeat domain-containing 7 α (Fbw7 α) causes hepatosteatosis through Krüppel-like Factor 5 (KLF5)/Peroxisome Proliferator-activated Receptor γ 2 (PPAR γ 2) pathway but not SREBP-1c protein in mice. Journal of Biological Chemistry 2011 286 47 40835 40846 2-s2.0-81755171440 10.1074/jbc.M111.235283
23. Gaemers C., Stallen J. M., Kunne C., Wallner C., van Werven J., Nederveen A., Lamers W. H., Lipotoxicity and steatohepatitis in an overfed mouse model for non-alcoholic fatty liver disease. Biochimica et Biophysica Acta 2011 1812 4 447 458 2-s2.0-79151469687 10.1016/j.bbadis.2011.01.003
24. Larter C. Z., Yeh M. M., Van Rooyen D. M., Teoh N. C., Brooling J., Hou J. Y., Williams J., Clyne M., Nolan C. J., Farrell G. C., Roles of adipose restriction and metabolic factors in progression of steatosis to steatohepatitis in obese, diabetic mice. Journal of Gastroenterology and Hepatology 2009 24 10 1658 1668 2-s2.0-70349684935 10.1111/j.1440-1746.2009.05996.x
25. He J., Lee J. H., Febbraio M., Xie W., The emerging roles of fatty acid translocase/CD36 and the aryl hydrocarbon receptor in fatty liver disease. Experimental Biology and Medicine 2011 236 10 1116 1121 2-s2.0-80053450975 10.1258/ebm.2011.011128
26. Kawano Y., Cohen D. E., Mechanisms of hepatic triglyceride accumulation in non-alcoholic fatty liver disease. Journal of Gastroenterology 2013 48 4 434 441 10.1007/s00535-013-0758-5
27. Videla L. A., Pettinelli P., Misregulation of PPAR functioning and its pathogenic consequences associated with nonalcoholic fatty liver disease in human obesity. PPAR Research 2012 2012 14 107434 10.1155/2012/107434
28. Nagasaka H., Miida T., Inui A., Inoue I., Tsukahara H., Komatsu H., Hiejima E., Fujisawa T., Yorifuji T., Hiranao K., Okajima H., Inomata Y., Fatty liver and anti-oxidant enzyme activities along with peroxisome proliferator-activated receptors γ and α expressions in the liver of Wilson's disease. Molecular Genetics and Metabolism 2012 107 3 542 547 10.1016/j.ymgme.2012.08.004
29. Matsusue K., Novel mechanism for hepatic lipid accumulation: a physiological role for hepatic PPAR γ -fsp27 signal. Yakugaku Zasshi 2012 132 7 823 829 10.1248/yakushi.132.823
30. Okumura T., Role of lipid droplet proteins in liver steatosis. Journal of Physiology and Biochemistry 2011 67 4 629 636 2-s2.0-84857394687
31. Panasyuk G., Espeillac C., Chauvin C., Pradelli L. A., Horie Y., Suzuki A., Annicotte J. -S., Fajas L., Foretz M., Verdeguer F., Pontoglio M., Ferré P., Scoazec J.-Y., Birnbaum M. J., Ricci J. -E., Pende M., PPAR γ contributes to PKM2 and HK2 expression in fatty liver. Nature Communications 2012 14 3 672 680
32. Semple R. K., Chatterjee V. K. K., O'Rahilly S., PPAR γ and human metabolic disease. Journal of Clinical Investigation 2006 116 3 581 589 2-s2.0-33644644599 10.1172/JCI28003 (Pubitemid 43326862)
33. Flach R. J., Qin H., Zhang L., Bennett A. M., Loss of mitogen-activated protein kinase phosphatase-1 protects from hepatic steatosis by repression of cell death-inducing DNA Fragmentation Factor A (DFFA)-like effector C (CIDEC)/fat-specific protein 27. Journal of Biological Chemistry 2011 286 25 22195 22202 2-s2.0-79959364257 10.1074/jbc.M110.210237
34. Matsusue K., A physiological role for fat specific protein 27/cell death-inducing DFF45-like effector C in adipose and liver. Biological and Pharmaceutical Bulletin 2010 33 3 346 350 2-s2.0-77649224298 10.1248/bpb.33.346
35. Bai L., Jia Y., Viswakarma N., Huang J., Vluggens A., Wolins N. E., Jafari N., Rao M. S., Borensztajn J., Yang G., Reddy J. K., Transcription coactivator mediator subunit MED1 Is required for the development of fatty liver in the mouse. Hepatology 2011 53 4 1164 1174 2-s2.0-79953744708 10.1002/hep.24155
36. Kim E., Li K., Lieu C., Tong S., Kawai S., Fukutomi T., Zhou Y., Wands J., Li J., Expression of apolipoprotein C-IV is regulated by Ku antigen/peroxisome proliferator-activated receptor γ complex and correlates with liver steatosis. Journal of Hepatology 2008 49 5 787 798 2-s2.0-53249142134 10.1016/j.jhep.2008.06.029
37. Larter C. Z., Yeh M. M., Williams J., Bell-Anderson K. S., Farrell G. C., MCD-induced steatohepatitis is associated with hepatic adiponectin resistance and adipogenic transformation of hepatocytes. Journal of Hepatology 2008 49 3 407 416 2-s2.0-48449096011 10.1016/j.jhep.2008.03.026
38. Handberg A., Højlund K., Gastaldelli A., Flyvbjerg A., Dekker J. M., Petrie J., Piatti P., Beck-Nielsen H., Plasma sCD36 is associated with markers of atherosclerosis, insulin resistance and fatty liver in a nondiabetic healthy population. Journal of Internal Medicine 2012 271 3 294 304 2-s2.0-84857628613 10.1111/j.1365-2796.2011.02442.x
39. Ring A., Le Lay S., Pohl J., Verkade P., Stremmel W., Caveolin-1 is required for fatty acid translocase (FAT/CD36) localization and function at the plasma membrane of mouse embryonic fibroblasts. Biochimica et Biophysica Acta 2006 1761 4 416 423 2-s2.0-33646835213 10.1016/j.bbalip.2006.03.016 (Pubitemid 43776458)
40. Ehehalt R., Sparla R., Kulaksiz H., Herrmann T., Füllekrug J., Stremmel W., Uptake of long chain fatty acids is regulated by dynamic interaction of FAT/CD36 with cholesterol/sphingolipid enriched microdomains (lipid rafts). BMC Cell Biology 2008 9 45 2-s2.0-51649099019 10.1186/1471-2121-9-45
41. Su X., Abumrad N. A., Cellular fatty acid uptake: a pathway under construction. Trends in Endocrinology and Metabolism 2009 20 2 72 77 2-s2.0-63749108094 10.1016/j.tem.2008.11.001
42. Chabowski A., Górski J., Luiken J. J. F. P., Glatz J. F. C., Bonen A., Evidence for concerted action of FAT/CD36 and FABPpm to increase fatty acid transport across the plasma membrane. Prostaglandins Leukotrienes and Essential Fatty Acids 2007 77 5-6 345 353 2-s2.0-36749103888 10.1016/j.plefa.2007.10.017 (Pubitemid 350214519)
43. Xu S., Jay A., Brunaldi K., Huang N., Hamilton J. A., CD36 enhances fatty acid uptake by increasing the rate of intracellular esterification but not transport across the plasma membrane. Biochemistry 2013 52 41 7254 7261 10.1021/bi400914c
44. Manteiga S., Choi K., Jayaraman A., Lee K., Systems biology of adipose tissue metabolism: regulation of growth, signaling and inflammation. Wiley Interdisciplinary Reviews Systems Biology and Medicine 2013 5 4 425 447 10.1002/wsbm.1213
45. Guo Y., Cordes K. R., Farese R. V. Jr., Walther T. C., Lipid droplets at a glance. Journal of Cell Science 2009 122 6 749 752 2-s2.0-66949160825 10.1242/jcs.037630
46. Rogue A., Spire C., Brun M., Claude N., Guillouzo A., Gene expression changes induced by PPAR gamma agonists in animal and human liver. PPAR Research 2010 2010 16 2-s2.0-78349261937 10.1155/2010/325183 325183
47. Musso G., Gambino R., Cassader M., Recent insights into hepatic lipid metabolism in non-alcoholic fatty liver disease (NAFLD). Progress in Lipid Research 2009 48 1 1 26 2-s2.0-57649214103 10.1016/j.plipres.2008.08.001
48. Park C.-Y., Park S. W., Role of peroxisome proliferator-activated receptor gamma agonist in improving hepatic steatosis: possible molecular mechanism. Journal of Diabetes Investigation 2012 3 2 93 95 2-s2.0-84859114508 10.1111/j.2040-1124.2012.00204.x
49. He Z., Zhu H. H., Bauler T. J., Wang J., Ciaraldi T., Alderson N., Li S., Raquil M. A., Ji K., Wang S., Shao J., Henry R. R., King P. D., Feng G. S., Nonreceptor tyrosine phosphatase Shp2 promotes adipogenesis through inhibition of p38 MAP kinase. Proceedings of the National Academy of Sciences of the USA 2013 110 1 E79 E88 10.1073/pnas.1213000110
50. Chen W., Chang B., Saha P., Hartig S. M., Li L., Reddy V. T., Yang Y., Yechoor V., Mancini M. A., Chan L., Berardinelli-seip congenital lipodystrophy 2/seipin is a cell-autonomous regulator of lipolysis essential for adipocyte differentiation. Molecular and Cellular Biology 2012 32 6 1099 1111 2-s2.0-84857889290 10.1128/MCB.06465-11
51. Weismann D., Erion D. M., Ignatova-Todorava I., Nagai Y., Stark R., Hsiao J. J., Flannery C., Birkenfeld A. L., May T., Kahn M., Zhang D., Yu X. X., Murray S. F., Bhanot S., Monia B. P., Cline G. W., Shulman G. I., Samuel V. T., Knockdown of the gene encoding Drosophila tribbles homologue 3 (Trib3) improves insulin sensitivity through peroxisome proliferator-activated receptor- γ (PPAR- γ) activation in a rat model of insulin resistance. Diabetologia 2011 54 4 935 944 2-s2.0-79953812287 10.1007/s00125-010-1984-5
52. Tsukahara T., Tsukahara R., Fujiwara Y., Yue J., Cheng Y., Guo H., Bolen A., Zhang C., Balazs L., Re F., Du G., Frohman M. A., Baker D. L., Parrill A. L., Uchiyama A., Kobayashi T., Murakami-Murofushi K., Tigyi G., Phospholipase D2-dependent inhibition of the nuclear hormone receptor PPAR γ by cyclic phosphatidic acid. Molecular Cell 2010 39 3 421 432 2-s2.0-77955497628 10.1016/j.molcel.2010.07.022
53. Noh J.-R., Kim Y.-H., Hwang J.-H., Gang G. T., Yeo S. H., Kim K. S., Oh W. K., Ly S. Y., Lee I. K., Lee C. H., Scoparone inhibits adipocyte differentiation through down-regulation of peroxisome proliferators-activated receptor γ in 3T3-L1 preadipocytes. Food Chemistry 2013 141 2 723 730 10.1016/j.foodchem.2013.04.036
54. Anderson N., Borlak J., Molecular mechanisms and therapeutic targets in steatosis and steatohepatitis. Pharmacological Reviews 2008 60 3 311 357 2-s2.0-54049150442 10.1124/pr.108.00001
55. Chen H., Zhang L., Li X., Li X., Sun G., Yuan X., Lei L., Liu J., Yin L., Deng Q., Wang J., Liu Z., Yang W., Wang Z., Zhang H., Liu G., Adiponectin activates the AMPK signaling pathway to regulate lipid metabolism in bovine hepatocytes. Journal of Steroid Biochemistry and Molecular Biology 2013 138 445 454 10.1016/j.jsbmb.2013.08.013
56. Kursawe R., Narayan D., Cali A. M. G., Shaw M., Pierpont B., Shulman G. I., Caprio S., Downregulation of ADIPOQ and PPAR γ 2 gene expression in subcutaneous adipose tissue of obese adolescents with hepatic steatosis. Obesity 2010 18 10 1911 1917 2-s2.0-77957103200 10.1038/oby.2010.23
57. Wang Z., Dou X., Gu D., Shen C., Yao T., Nguyen V., Braunschweig C., Song Z., 4-Hydroxynonenal differentially regulates adiponectin gene expression and secretion via activating PPAR γ and accelerating ubiquitin-proteasome degradation. Molecular and Cellular Endocrinology 2012 349 2 222 231 2-s2.0-81555230837 10.1016/j.mce.2011.10.027
58. Lefils-Lacourtablaise J., Socorro M., Géloën A., Daira P., Debard C., Loizon E., Guichardant M., Dominguez Z., Vidal H., Lagarde M., Bernoud-Hubac N., The eicosapentaenoic acid metabolite 15-deoxy- δ (12,14)-prostaglandin J3 increases adiponectin secretion by adipocytes partly via a PPAR γ -dependent mechanism. PloS ONE 2013 8 5 e63997 10.1371/journal.pone.0063997
59. Greenberg A. S., Coleman R. A., Kraemer F. B., McManaman J. L., Obin M. S., Puri V., Yan Q., Miyoshi H., Mashek D. G., The role of lipid droplets in metabolic disease in rodents and humans. Journal of Clinical Investigation 2011 121 6 2102 2110 2-s2.0-79957889560 10.1172/JCI46069
60. Gwon S. Y., Ahn J. Y., Kim T. W., Ha T. Y., Zanthoxylum piperitum DC ethanol extract suppresses fat accumulation in adipocytes and high fat diet-induced obese mice by regulating adipogenesis. Journal of Nutritional Science and Vitaminology (Tokyo) 2012 58 6 393 401 10.3177/jnsv.58.393
61. Kang S.-I., Kim M.-H., Shin H.-S., Kim H., Hong Y., Park J., Ko H., Lee N., Chung W., Kim S., A water-soluble extract of Petalonia binghamiae inhibits the expression of adipogenic regulators in 3T3-L1 preadipocytes and reduces adiposity and weight gain in rats fed a high-fat diet. Journal of Nutritional Biochemistry 2010 21 12 1251 1257 2-s2.0-78249268815 10.1016/j.jnutbio.2009.11. 008
62. Park J.-E., Oh S.-H., Cha Y.-S., Lactobacillus plantarum LG42 isolated from gajami Sik-Hae inhibits adipogenesis in 3T3-L1 adipocyte. BioMed Research International 2013 2013 7 460927 10.1155/2013/460927
63. Xu J., Kulkarni S. R., Donepudi A. C., More V. R., Slitt A. L., Enhanced Nrf2 activity worsens insulin resistance, impairs lipid accumulation in adipose tissue, and increases hepatic steatosis in leptin-deficient mice. Diabetes 2012 61 12 3208 3218 10.2337/db11-1716
64. Liao Z., Dong J., Wu W., Yang T., Wang T., Guo L., Chen L., Xu D., Wen F., Resolvin D1 attenuates inflammation in lipopolysaccharide-induced acute lung injury through a process involving the PPAR γ /NF- B pathway. Respiratory Research 2012 13 110 10.1186/1465-9921-13-110
65. Magliano D. C., Bargut T. C., de Carvalho S. N., Aguila M. B., Mandarim-de-Lacerda C. A., Souza-Mello V., Peroxisome proliferator-activated receptors-alpha and gamma are targets to treat offspring from maternal diet-induced obesity in mice. PLoS ONE 2013 8 5 e64258 10.1371/journal.pone. 0064258
66. Neuschwander-Tetri B. A., Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: the central role of nontriglyceride fatty acid metabolites. Hepatology 2010 52 2 774 788 2-s2.0-77955690182 10.1002/hep.23719
67. Serviddio G., Bellanti F., Vendemiale G., Free radical biology for medicine: learning from nonalcoholic fatty liver disease. Free Radical Biology and Medicine C 2013 65 952 968
68. Polvani S., Tarocchi M., Galli A., PPAR and oxidative stress: Con(β) catenating NRF2 and FOXO. PPAR Research 2012 2012 15 2-s2.0-84859762514 10.1155/2012/641087 641087
69. Bugge A., Mandrup S., Molecular mechanisms and genome-wide aspects of PPAR subtype specific transactivation. PPAR Research 2010 2010 12 2-s2.0-77957933413 10.1155/2010/169506 169506
70. Schupp M., Lazar M. A., Endogenous ligands for nuclear receptors: digging deeper. Journal of Biological Chemistry 2010 285 52 40409 40415 2-s2.0-78650317248 10.1074/jbc.R110.182451
71. Burgermeister E., Seger R., MAPK kinases as nucleo-cytoplasmic shuttles for PPAR γ Cell Cycle 2007 6 13 1539 1548 2-s2.0-34548289084 (Pubitemid 47327937)
72. Houck K. A., Richard A. M., Judson R. S., Martin M. T., Reif D. M., Shah I., Steinberg P., ToxCast: predicting toxicity potential through high-throughput bioactivity profiling. High-Throughput ScreenIng Methods in Toxicity TestIng 2013 Hoboken, NJ, USA John Wiley & Sons 1 31