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BioMed Research International
Volume 2015 (2015), Article ID 597134, 10 pages
http://dx.doi.org/10.1155/2015/597134
Review Article

The Dual Role of Nrf2 in Nonalcoholic Fatty Liver Disease: Regulation of Antioxidant Defenses and Hepatic Lipid Metabolism

1Basic and Clinical Research on Iron Biology Group, Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Rua do Campo Alegre 823, 4150180 Porto, Portugal
2Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal

Received 10 October 2014; Revised 16 January 2015; Accepted 19 January 2015

Academic Editor: Maria Carmen Collado

Copyright © 2015 Sílvia S. Chambel et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. J. Huang, J. Borensztajn, and J. K. Reddy, “Hepatic lipid metabolism,” in Molecular Pathology of Liver Diseases, S. P. S. Monga, Ed., vol. 5, pp. 133–146, Springer, Berlin, Germany, 2011. View at Publisher · View at Google Scholar
  2. G. Serviddio, F. Bellanti, and G. Vendemiale, “Free radical biology for medicine: learning from nonalcoholic fatty liver disease,” Free Radical Biology and Medicine, vol. 65, pp. 952–968, 2013. View at Publisher · View at Google Scholar · View at Scopus
  3. Y. Stein and B. Shapiro, “Uptake and metabolism of triglycerides by the rat liver,” Journal of Lipid Research, vol. 1, pp. 326–331, 1960. View at Google Scholar · View at Scopus
  4. K. Liu and M. J. Czaja, “Regulation of lipid stores and metabolism by lipophagy,” Cell Death and Differentiation, vol. 20, no. 1, pp. 3–11, 2013. View at Publisher · View at Google Scholar · View at Scopus
  5. V. Zámbó, L. Simon-Szabó, P. Szelényi, É. Kereszturi, G. Bánhegyi, and M. Csala, “Lipotoxicity in the liver,” World Journal of Hepatology, vol. 5, no. 10, pp. 550–557, 2013. View at Google Scholar · View at Scopus
  6. E. L. Seifert, C. Estey, J. Y. Xuan, and M.-E. Harper, “Electron transport chain-dependent and -independent mechanisms of mitochondrial H2O2 emission during long-chain fatty acid oxidation,” The Journal of Biological Chemistry, vol. 285, no. 8, pp. 5748–5758, 2010. View at Publisher · View at Google Scholar · View at Scopus
  7. G. Vial, H. Dubouchaud, K. Couturier et al., “Effects of a high-fat diet on energy metabolism and ROS production in rat liver,” Journal of Hepatology, vol. 54, no. 2, pp. 348–356, 2011. View at Publisher · View at Google Scholar · View at Scopus
  8. A. K. Leamy, R. A. Egnatchik, and J. D. Young, “Molecular mechanisms and the role of saturated fatty acids in the progression of non-alcoholic fatty liver disease,” Progress in Lipid Research, vol. 52, no. 1, pp. 165–174, 2013. View at Publisher · View at Google Scholar · View at Scopus
  9. E. S. Ford, W. H. Giles, and W. H. Dietz, “Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey,” The Journal of the American Medical Association, vol. 287, no. 3, pp. 356–359, 2002. View at Publisher · View at Google Scholar · View at Scopus
  10. D. M. Boudreau, D. C. Malone, M. A. Raebel et al., “Health care utilization and costs by metabolic syndrome risk factors,” Metabolic Syndrome and Related Disorders, vol. 7, no. 4, pp. 305–313, 2009. View at Publisher · View at Google Scholar · View at Scopus
  11. K. G. M. M. Alberti, P. Zimmet, and J. Shaw, “Metabolic syndrome—a new world-wide definition. A Consensus Statement from the International Diabetes Federation,” Diabetic Medicine, vol. 23, no. 5, pp. 469–480, 2006. View at Publisher · View at Google Scholar · View at Scopus
  12. P. Dietrich and C. Hellerbrand, “Non-alcoholic fatty liver disease, obesity and the metabolic syndrome,” Best Practice & Research Clinical Gastroenterology, vol. 28, no. 4, pp. 637–653, 2014. View at Publisher · View at Google Scholar
  13. K. I. Tong, A. Kobayashi, F. Katsuoka, and M. Yamamoto, “Two-site substrate recognition model for the Keap1-Nrf2 system: a hinge and latch mechanism,” The Journal of Biological Chemistry, vol. 387, no. 10-11, pp. 1311–1320, 2006. View at Publisher · View at Google Scholar · View at Scopus
  14. C. P. Day and O. F. W. James, “Hepatic steatosis: innocent bystander or guilty party?” Hepatology, vol. 27, no. 6, pp. 1463–1466, 1998. View at Publisher · View at Google Scholar · View at Scopus
  15. S.-J. Lee, J. Zhang, A. M. K. Choi, and H. P. Kim, “Mitochondrial dysfunction induces formation of lipid droplets as a generalized response to stress,” Oxidative Medicine and Cellular Longevity, vol. 2013, Article ID 327167, 10 pages, 2013. View at Publisher · View at Google Scholar · View at Scopus
  16. M. Amir and M. J. Czaja, “Autophagy in nonalcoholic steatohepatitis,” Expert Review of Gastroenterology and Hepatology, vol. 5, no. 2, pp. 159–166, 2011. View at Publisher · View at Google Scholar · View at Scopus
  17. Z. Tariq, C. J. Green, and L. Hodson, “Are oxidative stress mechanisms the common denominator in the progression from hepatic steatosis towards non-alcoholic steatohepatitis (NASH)?” Liver International, vol. 34, no. 7, pp. e180–e190, 2014. View at Publisher · View at Google Scholar · View at Scopus
  18. Y.-K. J. Zhang, R. L. Yeager, Y. Tanaka, and C. D. Klaassen, “Enhanced expression of Nrf2 in mice attenuates the fatty liver produced by a methionine- and choline-deficient diet,” Toxicology and Applied Pharmacology, vol. 245, no. 3, pp. 326–334, 2010. View at Publisher · View at Google Scholar · View at Scopus
  19. M. S. Yates, Q. T. Tran, P. M. Dolan et al., “Genetic versus chemoprotective activation of Nrf2 signaling: overlapping yet distinct gene expression profiles between Keap1 knockout and triterpenoid-treated mice,” Carcinogenesis, vol. 30, no. 6, pp. 1024–1031, 2009. View at Publisher · View at Google Scholar · View at Scopus
  20. N. R. Kitteringham, A. Abdullah, J. Walsh et al., “Proteomic analysis of Nrf2 deficient transgenic mice reveals cellular defence and lipid metabolism as primary Nrf2-dependent pathways in the liver,” Journal of Proteomics, vol. 73, no. 8, pp. 1612–1631, 2010. View at Publisher · View at Google Scholar · View at Scopus
  21. Y. Tanaka, L. M. Aleksunes, R. L. Yeager et al., “NF-E2-related factor 2 inhibits lipid accumulation and oxidative stress in mice fed a high-fat diet,” Journal of Pharmacology and Experimental Therapeutics, vol. 325, no. 2, pp. 655–664, 2008. View at Publisher · View at Google Scholar · View at Scopus
  22. Y. Tanaka, T. Ikeda, K. Yamamoto, H. Ogawa, and T. Kamisako, “Dysregulated expression of fatty acid oxidation enzymes and iron-regulatory genes in livers of Nrf2-null mice,” Journal of Gastroenterology and Hepatology, vol. 27, no. 11, pp. 1711–1717, 2012. View at Publisher · View at Google Scholar · View at Scopus
  23. Y.-K. J. Zhang, K. C. Wu, J. Liu, and C. D. Klaassen, “Nrf2 deficiency improves glucose tolerance in mice fed a high-fat diet,” Toxicology and Applied Pharmacology, vol. 264, no. 3, pp. 305–314, 2012. View at Publisher · View at Google Scholar · View at Scopus
  24. S. Shin, J. Wakabayashi, M. S. Yates et al., “Role of Nrf2 in prevention of high-fat diet-induced obesity by synthetic triterpenoid CDDO-Imidazolide,” European Journal of Pharmacology, vol. 620, no. 1–3, pp. 138–144, 2009. View at Publisher · View at Google Scholar · View at Scopus
  25. J. Huang, I. Tabbi-Anneni, V. Gunda, and L. Wang, “Transcription factor Nrf2 regulates SHP and lipogenic gene expression in hepatic lipid metabolism,” The American Journal of Physiology—Gastrointestinal and Liver Physiology, vol. 299, no. 6, pp. G1211–G1221, 2010. View at Publisher · View at Google Scholar · View at Scopus
  26. P. K. Saha, V. T. Reddy, M. Konopleva, M. Andreeff, and L. Chan, “The triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic-acid methyl ester has potent anti-diabetic effects in diet-induced diabetic mice and Leprdb/db mice,” The Journal of Biological Chemistry, vol. 285, no. 52, pp. 40581–40592, 2010. View at Publisher · View at Google Scholar · View at Scopus
  27. C. J. Oh, J.-Y. Kim, A.-K. Min et al., “Sulforaphane attenuates hepatic fibrosis via NF-E2-related factor 2-mediated inhibition of transforming growth factor-β/Smad signaling,” Free Radical Biology and Medicine, vol. 52, no. 3, pp. 671–682, 2012. View at Publisher · View at Google Scholar · View at Scopus
  28. K. Okada, E. Warabi, H. Sugimoto et al., “Nrf2 inhibits hepatic iron accumulation and counteracts oxidative stress-induced liver injury in nutritional steatohepatitis,” Journal of Gastroenterology, vol. 47, no. 8, pp. 924–935, 2012. View at Publisher · View at Google Scholar · View at Scopus
  29. R. Shimozono, Y. Asaoka, Y. Yoshizawa et al., “Nrf2 activators attenuate the progression of nonalcoholic steatohepatitis-related fibrosis in a dietary rat models,” Molecular Pharmacology, vol. 84, no. 1, pp. 62–70, 2013. View at Publisher · View at Google Scholar · View at Scopus
  30. A.-L. Levonen, B. G. Hill, E. Kansanen, J. Zhang, and V. M. Darley-Usmar, “Redox regulation of antioxidants, autophagy, and the response to stress: implications for electrophile therapeutics,” Free Radical Biology and Medicine, vol. 71, pp. 196–207, 2014. View at Publisher · View at Google Scholar · View at Scopus
  31. A. T. Dinkova-Kostova, W. D. Holtzclaw, and T. W. Kensler, “The role of Keap1 in cellular protective responses,” Chemical Research in Toxicology, vol. 18, no. 12, pp. 1779–1791, 2005. View at Publisher · View at Google Scholar · View at Scopus
  32. T. H. Rushmore, M. R. Morton, and C. B. Pickett, “The antioxidant responsive element: activation by oxidative stress and identification of the DNA consensus sequence required for functional activity,” Journal of Biological Chemistry, vol. 266, no. 18, pp. 11632–11639, 1991. View at Google Scholar · View at Scopus
  33. W. W. Wasserman and W. E. Fahl, “Functional antioxidant responsive elements,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 10, pp. 5361–5366, 1997. View at Publisher · View at Google Scholar · View at Scopus
  34. T. Nguyen, P. J. Sherratt, and C. B. Pickett, “Regulatory mechanisms controlling gene expression mediated by the antioxidant response element,” Annual Review of Pharmacology and Toxicology, vol. 43, pp. 233–260, 2003. View at Publisher · View at Google Scholar · View at Scopus
  35. J.-M. Lee, M. J. Calkins, K. Chan, Y. W. Kan, and J. A. Johnson, “Identification of the NF-E2-related factor-2-dependent genes conferring protection against oxidative stress in primary cortical astrocytes using oligonucleotide microarray analysis,” The Journal of Biological Chemistry, vol. 278, no. 14, pp. 12029–12038, 2003. View at Publisher · View at Google Scholar · View at Scopus
  36. T. W. Kensler, N. Wakabayashi, and S. Biswal, “Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway,” Annual Review of Pharmacology and Toxicology, vol. 47, pp. 89–116, 2007. View at Publisher · View at Google Scholar · View at Scopus
  37. T. Suzuki, H. Motohashi, and M. Yamamoto, “Toward clinical application of the Keap1-Nrf2 pathway,” Trends in Pharmacological Sciences, vol. 34, no. 6, pp. 340–346, 2013. View at Publisher · View at Google Scholar · View at Scopus
  38. E. Kansanen, H.-K. Jyrkkänen, and A.-L. Levonen, “Activation of stress signaling pathways by electrophilic oxidized and nitrated lipids,” Free Radical Biology and Medicine, vol. 52, no. 6, pp. 973–982, 2012. View at Publisher · View at Google Scholar · View at Scopus
  39. P. Rada, A. I. Rojo, S. Chowdhry, M. McMahon, J. D. Hayes, and A. Cuadrado, “SCF/β-TrCP promotes glycogen synthase kinase 3-dependent degradation of the Nrf2 transcription factor in a Keap1-independent manner,” Molecular and Cellular Biology, vol. 31, no. 6, pp. 1121–1133, 2011. View at Publisher · View at Google Scholar · View at Scopus
  40. S. B. Cullinan and J. A. Diehl, “Coordination of ER and oxidative stress signaling: the PERK/Nrf2 signaling pathway,” The International Journal of Biochemistry & Cell Biology, vol. 38, no. 3, pp. 317–332, 2006. View at Publisher · View at Google Scholar · View at Scopus
  41. W. Miao, L. Hu, P. J. Scrivens, and G. Batist, “Transcriptional regulation of NF-E2 p45-related factor (NRF2) expression by the aryl hydrocarbon receptor-xenobiotic response element signaling pathway: direct cross-talk between phase I and II drug-metabolizing enzymes,” The Journal of Biological Chemistry, vol. 280, no. 21, pp. 20340–20348, 2005. View at Publisher · View at Google Scholar · View at Scopus
  42. S. Tao, S. Wang, S. J. Moghaddam et al., “Oncogenic KRAS confers chemoresistance by upregulating NRF2,” Cancer Research, vol. 74, no. 24, pp. 7430–7441, 2014. View at Publisher · View at Google Scholar
  43. J. D. Hayes and A. T. Dinkova-Kostova, “The Nrf2 regulatory network provides an interface between redox and intermediary metabolism,” Trends in Biochemical Sciences, vol. 39, no. 4, pp. 199–218, 2014. View at Publisher · View at Google Scholar · View at Scopus
  44. W. O. Osburn and T. W. Kensler, “Nrf2 signaling: an adaptive response pathway for protection against environmental toxic insults,” Mutation Research—Reviews in Mutation Research, vol. 659, no. 1-2, pp. 31–39, 2008. View at Publisher · View at Google Scholar · View at Scopus
  45. H. Malhi and R. J. Kaufman, “Endoplasmic reticulum stress in liver disease,” Journal of Hepatology, vol. 54, no. 4, pp. 795–809, 2011. View at Publisher · View at Google Scholar · View at Scopus
  46. M. Komatsu, H. Kurokawa, S. Waguri et al., “The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1,” Nature Cell Biology, vol. 12, no. 3, pp. 213–223, 2010. View at Publisher · View at Google Scholar · View at Scopus
  47. J. Kwon, E. Han, C.-B. Bui et al., “Assurance of mitochondrial integrity and mammalian longevity by the p62-Keap1-Nrf2-Nqo1 cascade,” EMBO Reports, vol. 13, no. 2, pp. 150–156, 2012. View at Publisher · View at Google Scholar · View at Scopus
  48. K. M. Holmstrom, L. Baird, Y. Zhang et al., “Nrf2 impacts cellular bioenergetics by controlling substrate availability for mitochondrial respiration,” Biology Open, vol. 2, no. 8, pp. 761–770, 2013. View at Publisher · View at Google Scholar
  49. M. H. R. Ludtmann, P. R. Angelova, Y. Zhang, A. Y. Abramov, and A. T. Dinkova-Kostova, “Nrf2 affects the efficiency of mitochondrial fatty acid oxidation,” Biochemical Journal, vol. 457, no. 3, pp. 415–424, 2014. View at Publisher · View at Google Scholar · View at Scopus
  50. L. M. Aleksunes and J. E. Manautou, “Emerging role of Nrf2 in protecting against hepatic and gastrointestinal disease,” Toxicologic Pathology, vol. 35, no. 4, pp. 459–473, 2007. View at Publisher · View at Google Scholar · View at Scopus
  51. C. D. Klaassen and S. A. Reisman, “Nrf2 the rescue: effects of the antioxidative/electrophilic response on the liver,” Toxicology and Applied Pharmacology, vol. 244, no. 1, pp. 57–65, 2010. View at Publisher · View at Google Scholar · View at Scopus
  52. J. Liu, K. C. Wu, Y.-F. Lu, E. Ekuase, and C. D. Klaassen, “NRF2 protection against liver injury produced by various hepatotoxicants,” Oxidative Medicine and Cellular Longevity, vol. 2013, Article ID 305861, 8 pages, 2013. View at Publisher · View at Google Scholar · View at Scopus
  53. H. Lu, W. Cui, and C. D. Klaassen, “Nrf2 protects against 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced oxidative injury and steatohepatitis,” Toxicology and Applied Pharmacology, vol. 256, no. 2, pp. 122–135, 2011. View at Publisher · View at Google Scholar · View at Scopus
  54. W. Xu, C. Hellerbrand, U. A. Köhler et al., “The Nrf2 transcription factor protects from toxin-induced liver injury and fibrosis,” Laboratory Investigation, vol. 88, no. 10, pp. 1068–1078, 2008. View at Publisher · View at Google Scholar · View at Scopus
  55. S. Silva-Gomes, A. G. Santos, C. Caldas et al., “Transcription factor NRF2 protects mice against dietary iron-induced liver injury by preventing hepatocytic cell death,” Journal of Hepatology, vol. 60, no. 2, pp. 354–361, 2014. View at Publisher · View at Google Scholar · View at Scopus
  56. L. B. M. Tijburg, C. B. Nyathi, G. W. Meijer, and M. J. H. Geelen, “Biosynthesis and secretion of triacylglycerol in rat liver after partial hepatectomy,” The Biochemical Journal, vol. 277, no. 3, pp. 723–728, 1991. View at Google Scholar · View at Scopus
  57. E. P. Newberry, S. M. Kennedy, Y. Xie et al., “Altered hepatic triglyceride content after partial hepatectomy without impaired liver regeneration in multiple murine genetic models,” Hepatology, vol. 48, no. 4, pp. 1097–1105, 2008. View at Publisher · View at Google Scholar · View at Scopus
  58. I. García-Arcos, P. González-Kother, P. Aspichueta, Y. Rueda, B. Ochoa, and O. Fresnedo, “Lipid analysis reveals quiescent and regenerating liver-specific populations of lipid droplets,” Lipids, vol. 45, no. 12, pp. 1101–1108, 2010. View at Publisher · View at Google Scholar · View at Scopus
  59. T. A. Beyer, W. Xu, D. Teupser et al., “Impaired liver regeneration in Nrf2 knockout mice: Role of ROS-mediated insulin/IGF-1 resistance,” EMBO Journal, vol. 27, no. 1, pp. 212–223, 2008. View at Publisher · View at Google Scholar · View at Scopus
  60. R. Dayoub, A. Vogel, J. Schuett et al., “Nrf2 activates augmenter of liver regeneration (ALR) via antioxidant response element and links oxidative stress to liver regeneration,” Molecular Medicine, vol. 19, no. 1, pp. 237–244, 2013. View at Publisher · View at Google Scholar · View at Scopus
  61. F. Sheedfar, S. D. Biase, D. Koonen, and M. Vinciguerra, “Liver diseases and aging: friends or foes?” Aging Cell, vol. 12, no. 6, pp. 950–954, 2013. View at Publisher · View at Google Scholar · View at Scopus
  62. J. H. Suh, S. V. Shenvi, B. M. Dixon et al., “Decline in transcriptional activity of Nrf2 causes age-related loss of glutathione synthesis, which is reversible with lipoic acid,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 10, pp. 3381–3386, 2004. View at Publisher · View at Google Scholar · View at Scopus
  63. P.-H. Shih and G.-C. Yen, “Differential expressions of antioxidant status in aging rats: the role of transcriptional factor Nrf2 and MAPK signaling pathway,” Biogerontology, vol. 8, no. 2, pp. 71–80, 2007. View at Publisher · View at Google Scholar · View at Scopus
  64. A. Hirayama, K. Yoh, S. Nagase et al., “EPR imaging of reducing activity in Nrf2 transcriptional factor-deficient mice,” Free Radical Biology and Medicine, vol. 34, no. 10, pp. 1236–1242, 2003. View at Publisher · View at Google Scholar · View at Scopus
  65. A. R. Collins, C. J. Lyon, X. Xia et al., “Age-accelerated atherosclerosis correlates with failure to upregulate antioxidant genes,” Circulation Research, vol. 104, no. 6, pp. e42–e54, 2009. View at Publisher · View at Google Scholar · View at Scopus
  66. A. A. Gupte, C. J. Lyon, and W. A. Hsueh, “Nuclear factor (erythroid-derived 2)-like-2 factor (Nrf2), a key regulator of the antioxidant response to protect against atherosclerosis and nonalcoholic steatohepatitis,” Current Diabetes Reports, vol. 13, no. 3, pp. 362–371, 2013. View at Publisher · View at Google Scholar · View at Scopus
  67. R. N. Hardwick, C. D. Fisher, M. J. Canet, A. D. Lake, and N. J. Cherrington, “Diversity in antioxidant response enzymes in progressive stages of human nonalcoholic fatty liver disease,” Drug Metabolism and Disposition, vol. 38, no. 12, pp. 2293–2301, 2010. View at Publisher · View at Google Scholar · View at Scopus
  68. H. Sugimoto, K. Okada, J. Shoda et al., “Deletion of nuclear factor-E2-related factor-2 leads to rapid onset and progression of nutritional steatohepatitis in mice,” American Journal of Physiology: Gastrointestinal and Liver Physiology, vol. 298, no. 2, pp. G283–G294, 2010. View at Publisher · View at Google Scholar · View at Scopus
  69. S. Chowdhry, M. H. Nazmy, P. J. Meakin et al., “Loss of Nrf2 markedly exacerbates nonalcoholic steatohepatitis,” Free Radical Biology & Medicine, vol. 48, no. 2, pp. 357–371, 2010. View at Publisher · View at Google Scholar · View at Scopus
  70. C. Wang, Y. Cui, C. Li et al., “Nrf2 deletion causes “benign” simple steatosis to develop into nonalcoholic steatohepatitis in mice fed a high-fat diet,” Lipids in Health and Disease, vol. 12, no. 1, article 165, 2013. View at Publisher · View at Google Scholar · View at Scopus
  71. K. Okada, E. Warabi, H. Sugimoto et al., “Deletion of Nrf2 leads to rapid progression of steatohepatitis in mice fed atherogenic plus high-fat diet,” Journal of Gastroenterology, vol. 48, no. 5, pp. 620–632, 2013. View at Publisher · View at Google Scholar · View at Scopus
  72. Y. Zhang and G. B. Gordon, “A strategy for cancer prevention: stimulation of the Nrf2-ARE signaling pathway,” Molecular Cancer Therapeutics, vol. 3, no. 7, pp. 885–893, 2004. View at Google Scholar · View at Scopus
  73. A. T. Dinkova-Kostova, C. Abeygunawardana, and P. Talalay, “Chemoprotective properties of phenylpropenoids, bis(benzylidene)cycloalkanones, and related Michael reaction acceptors: correlation of potencies as phase 2 enzyme inducers and radical scavengers,” Journal of Medicinal Chemistry, vol. 41, no. 26, pp. 5287–5296, 1998. View at Publisher · View at Google Scholar · View at Scopus
  74. M. Ramos-Gomez, M.-K. Kwak, P. M. Dolan et al., “Sensitivity to carcinogenesis is increased and chemoprotective efficacy of enzyme inducers is lost in Nrf2 transcription factor-deficient mice,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 6, pp. 3410–3415, 2001. View at Publisher · View at Google Scholar · View at Scopus
  75. K. Liby, T. Hock, M. M. Yore et al., “The synthetic triterpenoids, CDDO and CDDO-imidazolide, are potent inducers of heme oxygenase-1 and Nrf2/ARE signaling,” Cancer Research, vol. 65, no. 11, pp. 4789–4798, 2005. View at Publisher · View at Google Scholar · View at Scopus
  76. K. Iida, K. Itoh, Y. Kumagai et al., “Nrf2 is essential for the chemopreventive efficacy of oltipraz against urinary bladder carcinogenesis,” Cancer Research, vol. 64, no. 18, pp. 6424–6431, 2004. View at Publisher · View at Google Scholar · View at Scopus
  77. J. Zhao, A. N. Moore, J. B. Redell, and P. K. Dash, “Enhancing expression of Nrf2-driven genes protects the blood-brain barrier after brain injury,” The Journal of Neuroscience, vol. 27, no. 38, pp. 10240–10248, 2007. View at Publisher · View at Google Scholar · View at Scopus
  78. M. S. Yates, M.-K. Kwak, P. A. Egner et al., “Potent protection against aflatoxin-induced tumorigenesis through induction of Nrf2-regulated pathways by the triterpenoid 1-[2-cyano-3-,12-dioxooleana-1, 9(11)-dien-28-oyl]imidazole,” Cancer Research, vol. 66, no. 4, pp. 2488–2494, 2006. View at Publisher · View at Google Scholar · View at Scopus
  79. A. M. Bataille and J. E. Manautou, “Nrf2: a potential target for new therapeutics in liver disease,” Clinical Pharmacology & Therapeutics, vol. 92, no. 3, pp. 340–348, 2012. View at Google Scholar · View at Scopus
  80. S. K. Nelson, S. K. Bose, G. K. Grunwald, P. Myhill, and J. M. McCord, “The induction of human superoxide dismutase and catalase in vivo: a fundamentally new approach to antioxidant therapy,” Free Radical Biology and Medicine, vol. 40, no. 2, pp. 341–347, 2006. View at Publisher · View at Google Scholar · View at Scopus
  81. L. Kappos, R. Gold, D. H. Miller et al., “Efficacy and safety of oral fumarate in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study,” The Lancet, vol. 372, no. 9648, pp. 1463–1472, 2008. View at Publisher · View at Google Scholar · View at Scopus
  82. P. E. Pergola, P. Raskin, R. D. Toto et al., “Bardoxolone methyl and kidney function in CKD with type 2 diabetes,” The New England Journal of Medicine, vol. 365, no. 4, pp. 327–336, 2011. View at Publisher · View at Google Scholar · View at Scopus
  83. M. S. Yates, M. Tauchi, F. Katsuoka et al., “Pharmacodynamic characterization of chemopreventive triterpenoids as exceptionally potent inducers of Nrf2-regulated genes,” Molecular Cancer Therapeutics, vol. 6, no. 1, pp. 154–162, 2007. View at Publisher · View at Google Scholar · View at Scopus
  84. W.-S. Jeong, Y.-S. Keum, C. Chen et al., “Differential expression and stability of endogenous nuclear factor E2-related factor 2 (Nrf2) by natural chemopreventive compounds in HepG2 human hepatoma cells,” Journal of Biochemistry and Molecular Biology, vol. 38, no. 2, pp. 167–176, 2005. View at Publisher · View at Google Scholar · View at Scopus
  85. T. Greco, J. Shafer, and G. Fiskum, “Sulforaphane inhibits mitochondrial permeability transition and oxidative stress,” Free Radical Biology and Medicine, vol. 51, no. 12, pp. 2164–2171, 2011. View at Publisher · View at Google Scholar · View at Scopus
  86. A. Nakamura and Y. Terauchi, “Lessons from mouse models of high-fat diet-induced NAFLD,” International Journal of Molecular Sciences, vol. 14, no. 11, pp. 21240–21257, 2013. View at Publisher · View at Google Scholar · View at Scopus