Nrf2 a potential target for new therapeutics in liver disease

Clinical Pharmacology and Therapeutics

Volumn 92, Issue 3, 2012, Pages 340-348

  Bataille, A M ^a   Manautou, J E ^a  

^a UNIVERSITY OF CONNECTICUT   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIOXIDANT; BARDOXOLONE; BARDOXOLONE METHYL; BENZO[A]PYRENE; COMPLEMENTARY DNA; FUMARIC ACID DIMETHYL ESTER; NUCLEAR ERYTHROID 2 RELATED FACTOR 2; OLTIPRAZ; PARACETAMOL; PLACEBO; PROTANDIM; SULFORAPHANE; TRANSCRIPTION FACTOR; TRANSCRIPTION FACTOR NRF2; UNCLASSIFIED DRUG; XENOBIOTIC AGENT;

ACUTE KIDNEY FAILURE; ALCOHOL LIVER DISEASE; AMINO ACID SEQUENCE; CELL PROTECTION; CHRONIC KIDNEY DISEASE; DETOXIFICATION; DIET SUPPLEMENTATION; DISEASE COURSE; DRUG MECHANISM; DRUG TARGETING; ELECTROPHILIC STRESS; FIBROSIS; GENE EXPRESSION; GENE IDENTIFICATION; GENE TARGETING; HUMAN; LIVER CIRRHOSIS; LIVER PROTECTION; MULTIPLE SCLEROSIS; NONALCOHOLIC FATTY LIVER; NONHUMAN; OXIDATIVE STRESS; PRIORITY JOURNAL; REVIEW; TOXIC HEPATITIS; TRANSCRIPTION INITIATION; UPREGULATION;

DRUG-INDUCED LIVER INJURY; FATTY LIVER; HUMANS; LIVER DISEASES; LIVER DISEASES, ALCOHOLIC; NF-E2-RELATED FACTOR 2;

EID: 84865429068     PISSN: 00099236     EISSN: 15326535     Source Type: Journal    
DOI: 10.1038/clpt.2012.110     Document Type: Review

References (75)

1. Moi, P., Chan, K., Asunis, I., Cao, A. & Kan, Y.W. Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region. Proc. Natl. Acad. Sci. USA. 91, 9926-9930 (1994). (Pubitemid 24311921)
2. Aleksunes, L.M. & Manautou, J.E. Emerging role of Nrf2 in protecting against hepatic and gastrointestinal disease. Toxicol. Pathol. 35, 459-473 (2007). (Pubitemid 46911886)
3. Itoh, K. et al. Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev. 13, 76-86 (1999). (Pubitemid 29045117)
4. Kobayashi, M. & Yamamoto, M. Molecular mechanisms activating the Nrf2-Keap1 pathway of antioxidant gene regulation. Antioxid. Redox Signal. 7, 385-394 (2005). (Pubitemid 40279806)
5. Itoh, K., Tong, K.I. & Yamamoto, M. Molecular mechanism activating Nrf2-Keap1 pathway in regulation of adaptive response to electrophiles. Free Radic. Biol. Med. 36, 1208-1213 (2004). (Pubitemid 38526314)
6. Venugopal, R. & Jaiswal, A.K. Nrf2 and Nrf1 in association with Jun proteins regulate antioxidant response element-mediated expression and coordinated induction of genes encoding detoxifying enzymes. Oncogene 17, 3145-3156 (1998). (Pubitemid 29020810)
7. Venugopal, R. & Jaiswal, A.K. Nrf1 and Nrf2 positively and c-Fos and Fra1 negatively regulate the human antioxidant response element-mediated expression of NAD(P)H:quinone oxidoreductase1 gene. Proc. Natl. Acad. Sci. USA 93, 14960-14965 (1996). (Pubitemid 26419078)
8. Baird, L. & Dinkova-Kostova, A.T. The cytoprotective role of the Keap1-Nrf2 pathway. Arch. Toxicol. 85, 241-272 (2011).
9. Rolo, A.P., Teodoro, J.S. & Palmeira, C.M. Role of oxidative stress in the pathogenesis of nonalcoholic steatohepatitis. Free Radic. Biol. Med. 52, 59-69 (2012).
10. Aldaba-Muruato, L.R., Moreno, M.G., Shibayama, M., Tsutsumi, V. & Muriel, P. Protective efects of allopurinol against acute liver damage and cirrhosis induced by carbon tetrachloride: modulation of NF-kappaB, cytokine production and oxidative stress. Biochim. Biophys. Acta 1820, 65-75 (2012).
11. Ivanov, A.V., Smirnova, O.A., Ivanova, O.N., Masalova, O.V., Kochetkov, S.N. & Isaguliants, M.G. Hepatitis C virus proteins activate NRF2/ARE pathway by distinct ROS-dependent and independent mechanisms in HUH7 cells. PLoS ONE 6, e24957 (2011).
12. Hagen, T.M. et al. Extensive oxidative DNA damage in hepatocytes of transgenic mice with chronic active hepatitis destined to develop hepatocellular carcinoma. Proc. Natl. Acad. Sci. USA 91, 12808-12812 (1994).
13. Chan, K., Lu, R., Chang, J.C. & Kan, Y.W. NRF2, a member of the NFE2 family of transcription factors, is not essential for murine erythropoiesis, growth, and development. Proc. Natl. Acad. Sci. USA 93, 13943-13948 (1996). (Pubitemid 26424225)
14. Enomoto, A. et al. High sensitivity of Nrf2 knockout mice to acetaminophen hepatotoxicity associated with decreased expression of ARE-regulated drug metabolizing enzymes and antioxidant genes. Toxicol. Sci. 59, 169-177 (2001). (Pubitemid 32117993)
15. Ramos-Gomez, M. et al. Sensitivity to carcinogenesis is increased and chemoprotective efcacy of enzyme inducers is lost in nrf2 transcription factor-defcient mice. Proc. Natl. Acad. Sci. USA 98, 3410-3415 (2001). (Pubitemid 32220859)
16. Ross, D. Quinone reductases multitasking in the metabolic world. Drug Metab. Rev. 36, 639-654 (2004). (Pubitemid 39453067)
17. Siegel, D. et al. NAD(P)H:quinone oxidoreductase 1: role as a superoxide scavenger. Mol. Pharmacol. 65, 1238-1247 (2004). (Pubitemid 38543494)
18. Smith, M.T. et al. Low NAD(P)H:quinone oxidoreductase activity is associated with increased risk of leukemia with MLL translocations in infants and children. Blood 100, 4590-4593 (2002). (Pubitemid 35429702)
19. Itoh, K. et al. An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem. Biophys. Res. Commun. 236, 313-322 (1997). (Pubitemid 27373291)
20. Ishii, T., Itoh, K. & Yamamoto, M. Roles of Nrf2 in activation of antioxidant enzyme genes via antioxidant responsive elements. Meth. Enzymol. 348, 182-190 (2002). (Pubitemid 41103109)
21. Chan, J.Y. & Kwong, M. Impaired expression of glutathione synthetic enzyme genes in mice with targeted deletion of the Nrf2 basic-leucine zipper protein. Biochim. Biophys. Acta 1517, 19-26 (2000).
22. Chanas, S.A. et al. Loss of the Nrf2 transcription factor causes a marked reduction in constitutive and inducible expression of the glutathione S-transferase Gsta1, Gsta2, Gstm1, Gstm2, Gstm3 and Gstm4 genes in the livers of male and female mice. Biochem. J. 365, 405-416 (2002). (Pubitemid 36135312)
23. Gong, P. et al. Activation of the mouse heme oxygenase-1 gene by 15-deoxy-Delta(12,14)-prostaglandin J(2) is mediated by the stress response elements and transcription factor Nrf2. Antioxid. Redox Signal. 4, 249-257 (2002). (Pubitemid 34517176)
24. Ishii, T. et al. Transcription factor Nrf2 coordinately regulates a group of oxidative stress-inducible genes in macrophages. J. Biol. Chem. 275, 16023-16029 (2000). (Pubitemid 30366908)
25. Reisman, S.A., Buckley, D.B., Tanaka, Y. & Klaassen, C.D. CDDO-Im protects from acetaminophen hepatotoxicity through induction of Nrf2-dependent genes. Toxicol. Appl. Pharmacol. 236, 109-114 (2009).
26. Hayashi, A., Suzuki, H., Itoh, K., Yamamoto, M. & Sugiyama, Y. Transcription factor Nrf2 is required for the constitutive and inducible expression of multidrug resistance-associated protein 1 in mouse embryo fbroblasts. Biochem. Biophys. Res. Commun. 310, 824-829 (2003). (Pubitemid 37188696)
27. Vollrath, V., Wielandt, A.M., Iruretagoyena, M. & Chianale, J. Role of Nrf2 in the regulation of the Mrp2 (ABCC2) gene. Biochem. J. 395, 599-609 (2006).
28. Maher, J.M. et al. Oxidative and electrophilic stress induces multidrug resistance-associated protein transporters via the nuclear factor-E2-related factor-2 transcriptional pathway. Hepatology 46, 1597-1610 (2007). (Pubitemid 350155541)
29. Aleksunes, L.M. et al. Induction of Mrp3 and Mrp4 transporters during acetaminophen hepatotoxicity is dependent on Nrf2. Toxicol. Appl. Pharmacol. 226, 74-83 (2008). (Pubitemid 350235582)
30. Yates, M.S. et al. Genetic versus chemoprotective activation of Nrf2 signaling: overlapping yet distinct gene expression profles between Keap1 knockout and triterpenoid-treated mice. Carcinogenesis 30, 1024-1031 (2009).
31. Cheng, Q. et al. Constitutive activation of nuclear factor-E2-related factor 2 induces biotransformation enzyme and transporter expression in livers of mice with hepatocyte-specifc deletion of Kelch-like ECH-associated protein 1. J. Biochem. Mol. Toxicol. 25, 320-329 (2011).
32. Aleksunes, L.M., Goedken, M.J., Rockwell, C.E., Thomale, J., Manautou, J.E. & Klaassen, C.D. Transcriptional regulation of renal cytoprotective genes by Nrf2 and its potential use as a therapeutic target to mitigate cisplatin-induced nephrotoxicity. J. Pharmacol. Exp. Ther. 335, 2-12 (2010).
33. Liu, M. et al. Transcription factor Nrf2 is protective during ischemic and nephrotoxic acute kidney injury in mice. Kidney Int. 76, 277-285 (2009).
34. Córdova, E.J., Velázquez-Cruz, R., Centeno, F., Baca, V. & Orozco, L. The NRF2 gene variant,-653G/A, is associated with nephritis in childhood-onset systemic lupus erythematosus. Lupus 19, 1237-1242 (2010).
35. Liu, J. et al. Protandim, a fundamentally new antioxidant approach in chemoprevention using mouse two-stage skin carcinogenesis as a model. PLoS One 4, e5284 (2009).
36. Kim, Y.R. et al. Oncogenic NRF2 mutations in squamous cell carcinomas of oesophagus and skin. J. Pathol. 220, 446-451 (2010).
37. Kappos, L. et al. Efcacy and safety of oral fumarate in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study. Lancet 372, 1463-1472 (2008).
38. Velmurugan, K., Alam, J., McCord, J.M. & Pugazhenthi, S. Synergistic induction of heme oxygenase-1 by the components of the antioxidant supplement Protandim. Free Radic. Biol. Med. 46, 430-440 (2009).
39. Nelson, S.K., Bose, S.K., Grunwald, G.K., Myhill, P. & McCord, J.M. The induction of human superoxide dismutase and catalase in vivo: a fundamentally new approach to antioxidant therapy. Free Radic. Biol. Med. 40, 341-347 (2006). (Pubitemid 43069358)
40. Qureshi, M.M. et al. The dietary supplement Protandim decreases plasma osteopontin and improves markers of oxidative stress in muscular dystrophy mdx mice. J. Diet. Suppl. 7, 159-178 (2010).
41. Pergola, P.E. et al. Efect of bardoxolone methyl on kidney function in patients with T2D and stage 3b-4 CKD. Am. J. Nephrol. 33, 469-476 (2011).
42. Haugen, E. & Nath, K.A. The involvement of oxidative stress in the progression of renal injury. Blood Purif. 17, 58-65 (1999). (Pubitemid 29403563)
43. Pergola, P.E. et al. Bardoxolone methyl and kidney function in CKD with type 2 diabetes. N. Engl. J. Med. 365, 327-336 (2011).
44. Rogacev, K.S., Bittenbring, J.T. & Fliser, D. Bardoxolone methyl, chronic kidney disease, and type 2 diabetes. N. Engl. J. Med. 365, 1745-6; reply, 1746 (2011).
45. Upadhyay, A., Sarnak, M.J. & Levey, A.S. Bardoxolone methyl, chronic kidney disease, and type 2 diabetes. N. Engl. J. Med. 365, 1746; reply, 1746-1746; reply, 1747 (2011).
46. McMahon, G.M. & Forman, J.P. Bardoxolone methyl, chronic kidney disease, and type 2 diabetes. N. Engl. J. Med. 365, 1746; reply, 1746-1746; reply, 1747 (2011).
47. Wu, Q.Q. et al. Bardoxolone methyl (BARD) ameliorates ischemic AKI and increases expression of protective genes Nrf2, PPARgamma, and HO-1. Am. J. Physiol. Renal Physiol. 300, F1180-F1192 (2011).
48. Yoon, H.Y., Kang, N.I., Lee, H.K., Jang, K.Y., Park, J.W. & Park, B.H. Sulforaphane protects kidneys against ischemia-reperfusion injury through induction of the Nrf2-dependent phase 2 enzyme. Biochem. Pharmacol. 75, 2214-2223 (2008).
49. Agyeman, A.S. et al. Transcriptomic and proteomic profling of KEAP1 disrupted and sulforaphane-treated human breast epithelial cells reveals common expression profles. Breast Cancer Res. Treat. 132, 175-187 (2012).
50. Liu, H., Dinkova-Kostova, A.T. & Talalay, P. Coordinate regulation of enzyme markers for infammation and for protection against oxidants and electrophiles. Proc. Natl. Acad. Sci. USA 105, 15926-15931 (2008).
51. Arias, I. et al. The Liver: Biology and Pathobiology 5th edn. (Wiley and Sons, Hoboken, NJ, 2009).
52. Begriche, K., Igoudjil, A., Pessayre, D. & Fromenty, B. Mitochondrial dysfunction in NASH: causes, consequences and possible means to prevent it. Mitochondrion 6, 1-28 (2006).
53. Marí, M. et al. Mitochondrial free cholesterol loading sensitizes to TNF-and Fas-mediated steatohepatitis. Cell Metab. 4, 185-198 (2006). (Pubitemid 44307975)
54. Houstis, N., Rosen, E.D. & Lander, E.S. Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature 440, 944-948 (2006).
55. Pan, M., Cederbaum, A.I., Zhang, Y.L., Ginsberg, H.N., Williams, K.J. & Fisher, E.A. Lipid peroxidation and oxidant stress regulate hepatic apolipoprotein B degradation and VLDL production. J. Clin. Invest. 113, 1277-1287 (2004). (Pubitemid 39069927)
56. Nobili, V. et al. Glutathione metabolism and antioxidant enzymes in patients afected by nonalcoholic steatohepatitis. Clin. Chim. Acta 355, 105-111 (2005).
57. Videla, L.A. et al. Oxidative stress-related parameters in the liver of nonalcoholic fatty liver disease patients. Clin. Sci. 106, 261-268 (2004). (Pubitemid 38365832)
58. Sugimoto, H. et al. Deletion of nuclear factor-E2-related factor-2 leads to rapid onset and progression of nutritional steatohepatitis in mice. Am. J. Physiol. Gastrointest. Liver Physiol. 298, G283-G294 (2010).
59. Shin, S. et al. Role of Nrf2 in prevention of high-fat diet-induced obesity by synthetic triterpenoid CDDO-imidazolide. Eur. J. Pharmacol. 620, 138-144 (2009).
60. Wakabayashi, N., Slocum, S.L., Skoko, J.J., Shin, S. & Kensler, T.W. When NRF2 talks, who's listening? Antioxid. Redox Signal. 13, 1649-1663 (2010).
61. Seldon, M.P. et al. Heme oxygenase-1 inhibits the expression of adhesion molecules associated with endothelial cell activation via inhibition of NF-kappaB RelA phosphorylation at serine 276. J. Immunol. 179, 7840-7851 (2007).
62. Rushworth, S.A., MacEwan, D.J. & O'Connell, M.A. Lipopolysaccharide- induced expression of NAD(P)H:quinone oxidoreductase 1 and heme oxygenase-1 protects against excessive infammatory responses in human monocytes. J. Immunol. 181, 6730-6737 (2008).
63. Oh, C.J. et al. Sulforaphane attenuates hepatic fbrosis via NF-E2-related factor 2-mediated inhibition of transforming growth factor-beta/Smad signaling. Free Radic. Biol. Med. 52, 671-682 (2012).
64. Choi, H.K. et al. Inhibition of liver fbrosis by solubilized coenzyme Q10: Role of Nrf2 activation in inhibiting transforming growth factor-beta1 expression. Toxicol. Appl. Pharmacol. 240, 377-384 (2009).
65. Svegliati-Baroni, G. et al. Early response of alpha2(I) collagen to acetaldehyde in human hepatic stellate cells is TGF-beta independent. Hepatology 42, 343-352 (2005). (Pubitemid 41061087)
66. Dey, A. & Cederbaum, A.I. Alcohol and oxidative liver injury. Hepatology 43, S63-S74 (2006).
67. Girre, C., Lucas, D., Hispard, E., Menez, C., Dally, S. & Menez, J.F. Assessment of cytochrome P4502E1 induction in alcoholic patients by chlorzoxazone pharmacokinetics. Biochem. Pharmacol. 47, 1503-1508 (1994). (Pubitemid 24167259)
68. Gong, P. & Cederbaum, A.I. Nrf2 is increased by CYP2E1 in rodent liver and HepG2 cells and protects against oxidative stress caused by CYP2E1. Hepatology 43, 144-153 (2006). (Pubitemid 43733601)
69. Lamlé, J. et al. Nuclear factor-eythroid 2-related factor 2 prevents alcohol-induced fulminant liver injury. Gastroenterology 134, 1159-1168 (2008).
70. Wu, K.C., Cui, J.Y. & Klaassen, C.D. Benefcial role of Nrf2 in regulating NADPH generation and consumption. Toxicol. Sci. 123, 590-600 (2011).
71. Bardag-Gorce, F., Oliva, J., Lin, A., Li, J., French, B.A. & French, S.W. Proteasome inhibitor up regulates liver antioxidative enzymes in rat model of alcoholic liver disease. Exp. Mol. Pathol. 90, 123-130 (2011).
72. Yeligar, S.M., Machida, K. & Kalra, V.K. Ethanol-induced HO-1 and NQO1 are diferentially regulated by HIF-1alpha and Nrf2 to attenuate infammatory cytokine expression. J. Biol. Chem. 285, 35359-35373 (2010).
73. Goldring, C.E. et al. Activation of hepatic Nrf2 in vivo by acetaminophen in CD-1 mice. Hepatology 39, 1267-1276 (2004). (Pubitemid 38569048)
74. Chan, K., Han, X.D. & Kan, Y.W. An important function of Nrf2 in combating oxidative stress: detoxifcation of acetaminophen. Proc. Natl. Acad. Sci. USA 98, 4611-4616 (2001). (Pubitemid 32295024)
75. Liu, F. et al. Increased susceptibility of Nrf2-null mice to 1-bromopropane-induced hepatotoxicity. Toxicol. Sci. 115, 596-606 (2010).