Skip to main content

Advertisement

SpringerLink
Log in

Nuclear Factor (Erythroid-Derived 2)-Like-2 Factor (Nrf2), a Key Regulator of the Antioxidant Response to Protect Against Atherosclerosis and Nonalcoholic Steatohepatitis

  • Macrovascular Complications in Diabetes (PD Reaven, Section Editor)
  • Published:
Current Diabetes Reports Aims and scope Submit manuscript

Abstract

Tissue oxidative stress is a common hallmark of atherosclerosis and non-alcoholic steatohepatitis (NASH), 2 conditions linked epidemiologically and pathophysiologically. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the master regulator of inducible antioxidant responses, that can attenuate cellular injury from oxidative stress induced by obesity and other redox insults. Nrf2 expression and activation is reduced in mouse and human vessels that harbor accelerated atherosclerosis and in livers with histologic criteria of NASH. Systemic antioxidants have thus been attractive therapeutic targets, but clinical trials have been largely unsuccessful in improving cardiovascular health. Macrophage-selective Nrf2 activation may, however, provide an approach to reduce vascular and hepatocyte injury without the complications of systemic antioxidants, since macrophages play key roles in the development and progression of both atherosclerosis and NASH. In this article, we review the common mechanisms of oxidative stress and inflammation in atherosclerosis and NASH, and discuss the role of Nrf2 in vascular and hepatocyte protection.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Voelker R. Escalating obesity rates pose health, budget threats. JAMA. 2012;308:1514.

    Article  PubMed  CAS  Google Scholar 

  2. Alkhouri N, Tamimi TA, Yerian L, Lopez R, Zein NN, Feldstein AE. The inflamed liver and atherosclerosis: a link between histologic severity of nonalcoholic fatty liver disease and increased cardiovascular risk. Dig Dis Sci. 2010;55:2644–50.

    Article  PubMed  Google Scholar 

  3. Lorenzo C, Williams K, Hunt KJ, Haffner SM. The National Cholesterol Education Program - Adult Treatment Panel III, International Diabetes Federation, and World Health Organization definitions of the metabolic syndrome as predictors of incident cardiovascular disease and diabetes. Diabetes Care. 2007;30:8–13.

    Article  PubMed  Google Scholar 

  4. Donato AJ, Eskurza I, Silver AE, Levy AS, Pierce GL, Gates PE, et al. Direct evidence of endothelial oxidative stress with aging in humans: relation to impaired endothelium-dependent dilation and upregulation of nuclear factor-kappaB. Circ Res. 2007;100:1659–66.

    Article  PubMed  CAS  Google Scholar 

  5. Shimada M, Hashimoto E, Kaneda H, Noguchi S, Hayashi N. Nonalcoholic steatohepatitis: risk factors for liver fibrosis. Hepatol Res. 2002;24:429–38.

    Article  PubMed  Google Scholar 

  6. Schrauwen P, Hesselink MK. Oxidative capacity, lipotoxicity, and mitochondrial damage in type 2 diabetes. Diabetes. 2004;53:1412–7.

    Article  PubMed  CAS  Google Scholar 

  7. Koves TR, Ussher JR, Noland RC, Slentz D, Mosedale M, Ilkayeva O, et al. Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. Cell Metab. 2008;7:45–56.

    Article  PubMed  CAS  Google Scholar 

  8. Anderson EJ, Lustig ME, Boyle KE, Woodlief TL, Kane DA, Lin CT, et al. Mitochondrial H2O2 emission and cellular redox state link excess fat intake to insulin resistance in both rodents and humans. J Clin Invest. 2009;119:573–81.

    Article  PubMed  CAS  Google Scholar 

  9. Huang S, Rutkowsky JM, Snodgrass RG, Ono-Moore KD, Schneider DA, Newman JW, et al. Saturated fatty acids activate TLR-mediated proinflammatory signaling pathways. J Lipid Res. 2012;53:2002–13.

    Article  PubMed  CAS  Google Scholar 

  10. Boden G, She P, Mozzoli M, Cheung P, Gumireddy K, Reddy P, et al. Free fatty acids produce insulin resistance and activate the proinflammatory nuclear factor-kappaB pathway in rat liver. Diabetes. 2005;54:3458–65.

    Article  PubMed  CAS  Google Scholar 

  11. Csont T, Bereczki E, Bencsik P, Fodor G, Gorbe A, Zvara A, et al. Hypercholesterolemia increases myocardial oxidative and nitrosative stress thereby leading to cardiac dysfunction in apoB-100 transgenic mice. Cardiovasc Res. 2007;76:100–9.

    Article  PubMed  CAS  Google Scholar 

  12. Rodrigo R, Prat H, Passalacqua W, Araya J, Guichard C, Bachler JP. Relationship between oxidative stress and essential hypertension. Hypertens Res. 2007;30:1159–67.

    Article  PubMed  CAS  Google Scholar 

  13. Gugliucci A. Glycation as the glucose link to diabetic complications. J Am Osteopath Assoc. 2000;100:621–34.

    PubMed  CAS  Google Scholar 

  14. Giacco F, Brownlee M. Oxidative stress and diabetic complications. Circ Res. 2010;107:1058–70.

    Article  PubMed  CAS  Google Scholar 

  15. Ramasamy R, Yan SF, Schmidt AM. Receptor for AGE (RAGE): signaling mechanisms in the pathogenesis of diabetes and its complications. Ann N Y Acad Sci. 2011;124388:102.

    Google Scholar 

  16. Goldin A, Beckman JA, Schmidt AM, Creager MA. Advanced glycation end products: sparking the development of diabetic vascular injury. Circulation. 2006;114:597–605.

    Article  PubMed  CAS  Google Scholar 

  17. Chung SS, Ho EC, Lam KS, Chung SK. Contribution of polyol pathway to diabetes-induced oxidative stress. J Am Soc Nephrol. 2003;14(8 Suppl 3):S233–6.

    Article  PubMed  CAS  Google Scholar 

  18. Geraldes P, King GL. Activation of protein kinase C isoforms and its impact on diabetic complications. Circ Res. 2010;106:1319–31.

    Article  PubMed  CAS  Google Scholar 

  19. King GL, Loeken MR. Hyperglycemia-induced oxidative stress in diabetic complications. Histochem Cell Biol. 2004;122:333–8.

    Article  PubMed  CAS  Google Scholar 

  20. Prior JO, Quinones MJ, Hernandez-Pampaloni M, Facta AD, Schindler TH, Sayre JW, et al. Coronary circulatory dysfunction in insulin resistance, impaired glucose tolerance, and type 2 diabetes mellitus. Circulation. 2005;111:2291–8.

    Article  PubMed  CAS  Google Scholar 

  21. Forstermann U. Nitric oxide and oxidative stress in vascular disease. Pflugers Arch. 2010;459:923–39.

    Article  PubMed  Google Scholar 

  22. Hsueh WA, Lyon CJ, Quinones MJ. Insulin resistance and the endothelium. Am J Med. 2004;117:109–17.

    Article  PubMed  CAS  Google Scholar 

  23. Kalupahana NS, Moustaid-Moussa N. The renin-angiotensin system: a link between obesity, inflammation and insulin resistance. Obes Rev. 2012;13:136–49.

    Article  PubMed  CAS  Google Scholar 

  24. Tummala PE, Chen XL, Sundell CL, Laursen JB, Hammes CP, Alexander RW, et al. Angiotensin II induces vascular cell adhesion molecule-1 expression in rat vasculature: a potential link between the renin-angiotensin system and atherosclerosis. Circulation. 1999;100:1223–9.

    Article  PubMed  CAS  Google Scholar 

  25. Chen XL, Tummala PE, Olbrych MT, Alexander RW, Medford RM. Angiotensin II induces monocyte chemoattractant protein-1 gene expression in rat vascular smooth muscle cells. Circ Res. 1998;83:952–9.

    Article  PubMed  CAS  Google Scholar 

  26. Peluso I, Morabito G, Urban L, Ioannone F, Serafini M. Oxidative stress in atherosclerosis development: the central role of LDL and oxidative burst. Endocr Metab Immune Disord Drug Targets. 2012;12:351–60.

    Google Scholar 

  27. • Scull CM, Tabas I. Mechanisms of ER stress-induced apoptosis in atherosclerosis. Arterioscler Thromb Vasc Biol. 2011;31:2792–7. This review provides a detailed description of the role of macrophage apoptosis in formation of necrotic lipid cores in advanced atherosclerosis.

    Article  PubMed  CAS  Google Scholar 

  28. Naghavi M, Libby P, Falk E, Casscells SW, Litovsky S, Rumberger J, et al. From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part I. Circulation. 2003;108:1664–72.

    Article  PubMed  Google Scholar 

  29. Steinhubl SR. Why have antioxidants failed in clinical trials? Am J Cardiol. 2008;101:14D–9D.

    Article  PubMed  CAS  Google Scholar 

  30. Salonen JT, Nyyssonen K, Salonen R, Lakka HM, Kaikkonen J, Porkkala-Sarataho E, et al. Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) study: a randomized trial of the effect of vitamins E and C on 3-year progression of carotid atherosclerosis. J Intern Med. 2000;248:377–86.

    Article  PubMed  CAS  Google Scholar 

  31. Zureik M, Galan P, Bertrais S, Mennen L, Czernichow S, Blacher J, et al. Effects of long-term daily low-dose supplementation with antioxidant vitamins and minerals on structure and function of large arteries. Arterioscler Thromb Vasc Biol. 2004;24:1485–91.

    Article  PubMed  CAS  Google Scholar 

  32. Hodis HN, Mack WJ, LaBree L, Mahrer PR, Sevanian A, Liu CR, et al. Alpha-tocopherol supplementation in healthy individuals reduces low-density lipoprotein oxidation but not atherosclerosis: the Vitamin E Atherosclerosis Prevention Study (VEAPS). Circulation. 2002;106:1453–9.

    Article  PubMed  CAS  Google Scholar 

  33. Forman HJ, Maiorino M, Ursini F. Signaling functions of reactive oxygen species. Biochemistry. 2010;49:835–42.

    Google Scholar 

  34. Dotan Y, Pinchuk I, Lichtenberg D, Leshno M. Decision analysis supports the paradigm that indiscriminate supplementation of vitamin E does more harm than good. Arterioscler Thromb Vasc Biol. 2009;29:1304–9.

    Article  PubMed  CAS  Google Scholar 

  35. Ristow M, Zarse K, Oberbach A, Kloting N, Birringer M, Kiehntopf M, et al. Antioxidants prevent health-promoting effects of physical exercise in humans. Proc Natl Acad Sci U S A. 2009;106:8665–70.

    Article  PubMed  CAS  Google Scholar 

  36. Salonen RM, Nyyssonen K, Kaikkonen J, Porkkala-Sarataho E, Voutilainen S, Rissanen TH, et al. Six-year effect of combined vitamin C and E supplementation on atherosclerotic progression: the Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) Study. Circulation. 2003;107:947–53.

    Article  PubMed  CAS  Google Scholar 

  37. Videla LA, Rodrigo R, Orellana M, Fernandez V, Tapia G, Quinones L, et al. Oxidative stress-related parameters in the liver of non-alcoholic fatty liver disease patients. Clin Sci. 2004;106:261–8.

    Article  PubMed  CAS  Google Scholar 

  38. Houstis N, Rosen ED, Lander ES. Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature. 2006;440:944–8.

    Article  PubMed  CAS  Google Scholar 

  39. Seki S, Kitada T, Yamada T, Sakaguchi H, Nakatani K, Wakasa K. In situ detection of lipid peroxidation and oxidative DNA damage in non-alcoholic fatty liver diseases. J Hepatol. 2002;37:56–62.

    Article  PubMed  CAS  Google Scholar 

  40. Yesilova Z, Yaman H, Oktenli C, Ozcan A, Uygun A, Cakir E, et al. Systemic markers of lipid peroxidation and antioxidants in patients with nonalcoholic fatty liver disease. Am J Gastroenterol. 2005;100:850–5.

    Article  PubMed  CAS  Google Scholar 

  41. Milic S, Stimac D. Nonalcoholic fatty liver disease/steatohepatitis: epidemiology, pathogenesis, clinical presentation and treatment. Dig Dis. 2012;30:158–62.

    Article  PubMed  Google Scholar 

  42. Malaguarnera M, Di Rosa M, Nicoletti F, Malaguarnera L. Molecular mechanisms involved in NAFLD progression. J Mol Med. 2009;87:679–95.

    Article  PubMed  CAS  Google Scholar 

  43. • Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010;362:1675–85. This study provides important clinical evidence for the benefits of Vitamin E against NASH.

    Article  PubMed  CAS  Google Scholar 

  44. Tong KI, Kobayashi A, Katsuoka F, Yamamoto M. Two-site substrate recognition model for the Keap1-Nrf2 system: a hinge and latch mechanism. Biol Chem. 2006;387:1311–20.

    Article  PubMed  CAS  Google Scholar 

  45. Yamamoto T, Suzuki T, Kobayashi A, Wakabayashi J, Maher J, Motohashi H, et al. Physiological significance of reactive cysteine residues of Keap1 in determining Nrf2 activity. Mol Cell Biol. 2008;28:2758–70.

    Article  PubMed  CAS  Google Scholar 

  46. Rushmore TH, Morton MR, Pickett CB. The antioxidant responsive element. Activation by oxidative stress and identification of the DNA consensus sequence required for functional activity. J Biol Chem. 1991;266:11632–9.

    PubMed  CAS  Google Scholar 

  47. Chorley BN, Campbell MR, Wang X, Karaca M, Sambandan D, Bangura F, et al. Identification of novel NRF2-regulated genes by ChIP-Seq: influence on retinoid X receptor alpha. Nucleic Acids Res. 2012;40:7416–29.

    Article  PubMed  CAS  Google Scholar 

  48. Kim JH, Choi YK, Lee KS, Cho DH, Baek YY, Lee DK, et al. Functional dissection of Nrf2-dependent phase II genes in vascular inflammation and endotoxic injury using Keap1 siRNA. Free Radic Biol Med. 2012;53:629–40.

    Article  PubMed  CAS  Google Scholar 

  49. Bae SH, Sung SH, Oh SY, Lim JM, Lee SK, Park YN, et al. Sestrins activate Nrf2 by promoting p62-dependent autophagic degradation of Keap1 and prevent oxidative liver damage. Cell Metab. 2013;17:73–84.

    Article  PubMed  CAS  Google Scholar 

  50. Clements CM, McNally RS, Conti BJ, Mak TW, Ting JP. DJ-1, a cancer- and Parkinson's disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2. Proc Natl Acad Sci U S A. 2006;103:15091–6.

    Article  PubMed  CAS  Google Scholar 

  51. Lev N, Roncevic D, Ickowicz D, Melamed E, Offen D. Role of DJ-1 in Parkinson's disease. J Mol Neurosci. 2006;29:215–25.

    Article  PubMed  CAS  Google Scholar 

  52. Wu KC, Cui JY, Klaassen CD. Effect of graded Nrf2 activation on phase-I and -II drug metabolizing enzymes and transporters in mouse liver. PLoS One. 2012;7:e39006.

    Article  PubMed  CAS  Google Scholar 

  53. Thimmulappa RK, Mai KH, Srisuma S, Kensler TW, Yamamoto M, Biswal S. Identification of Nrf2-regulated genes induced by the chemopreventive agent sulforaphane by oligonucleotide microarray. Cancer Res. 2002;62:5196–203.

    PubMed  CAS  Google Scholar 

  54. Cho HY, Reddy SP, Debiase A, Yamamoto M, Kleeberger SR. Gene expression profiling of NRF2-mediated protection against oxidative injury. Free Radic Biol Med. 2005;38:325–43.

    Article  PubMed  CAS  Google Scholar 

  55. Enomoto A, Itoh K, Nagayoshi E, Haruta J, Kimura T, O'Connor T, 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. 2001;59:169–77.

    Article  PubMed  CAS  Google Scholar 

  56. Okawa H, Motohashi H, Kobayashi A, Aburatani H, Kensler TW, Yamamoto M. Hepatocyte-specific deletion of the keap1 gene activates Nrf2 and confers potent resistance against acute drug toxicity. Biochem Biophys Res Commun. 2006;339:79–88.

    Article  PubMed  CAS  Google Scholar 

  57. Ramos-Gomez M, Kwak MK, Dolan PM, Itoh K, Yamamoto M, Talalay P, et al. Sensitivity to carcinogenesis is increased and chemoprotective efficacy of enzyme inducers is lost in nrf2 transcription factor-deficient mice. Proc Natl Acad Sci U S A. 2001;98:3410–5.

    Article  PubMed  CAS  Google Scholar 

  58. Rangasamy T, Cho CY, Thimmulappa RK, Zhen L, Srisuma SS, Kensler TW, et al. Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke-induced emphysema in mice. J Clin Invest. 2004;114:1248–59.

    PubMed  CAS  Google Scholar 

  59. Thimmulappa RK, Lee H, Rangasamy T, Reddy SP, Yamamoto M, Kensler TW, et al. Nrf2 is a critical regulator of the innate immune response and survival during experimental sepsis. J Clin Invest. 2006;116:984–95.

    Article  PubMed  CAS  Google Scholar 

  60. Chan K, Kan YW. Nrf2 is essential for protection against acute pulmonary injury in mice. Proc Natl Acad Sci U S A. 1999;96:12731–6.

    Article  PubMed  CAS  Google Scholar 

  61. Andres-Mateos E, Perier C, Zhang L, Blanchard-Fillion B, Greco TM, Thomas B, et al. DJ-1 gene deletion reveals that DJ-1 is an atypical peroxiredoxin-like peroxidase. Proc Natl Acad Sci U S A. 2007;104:14807–12.

    Article  PubMed  CAS  Google Scholar 

  62. Pi J, Leung L, Xue P, Wang W, Hou Y, Liu D, et al. Deficiency in the nuclear factor E2-related factor-2 transcription factor results in impaired adipogenesis and protects against diet-induced obesity. J Biol Chem. 2010;285:9292–300.

    Article  PubMed  CAS  Google Scholar 

  63. Chartoumpekis DV, Ziros PG, Psyrogiannis AI, Papavassiliou AG, Kyriazopoulou VE, Sykiotis GP, et al. Nrf2 represses FGF21 during long-term high-fat diet-induced obesity in mice. Diabetes. 2011;60:2465–73.

    Article  PubMed  CAS  Google Scholar 

  64. Kharitonenkov A, Shiyanova TL, Koester A, Ford AM, Micanovic R, Galbreath EJ, et al. FGF-21 as a novel metabolic regulator. J Clin Invest. 2005;115:1627–35.

    Article  PubMed  CAS  Google Scholar 

  65. Meher AK, Sharma PR, Lira VA, Yamamoto M, Kensler TW, Yan Z, et al. Nrf2 deficiency in myeloid cells is not sufficient to protect mice from high-fat diet-induced adipose tissue inflammation and insulin resistance. Free Radic Biol Med. 2012;52:1708–15.

    Article  PubMed  CAS  Google Scholar 

  66. •• Collins AR, Gupte AA, Ji R, Ramirez MR, Minze LJ, Liu JZ, et al. Myeloid deletion of Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) increases atherosclerosis and liver injury. Arterioscler Thromb Vasc Biol. 2012;32:2839–46. This study provides important evidence for the role of myeloid Nrf2 in protection from atherosclerosis and liver injury.

    Article  PubMed  CAS  Google Scholar 

  67. Shin S, Wakabayashi N, Misra V, Biswal S, Lee GH, Agoston ES, et al. NRF2 modulates aryl hydrocarbon receptor signaling: influence on adipogenesis. Mol Cell Biol. 2007;27:7188–97.

    Article  PubMed  CAS  Google Scholar 

  68. Shin S, Wakabayashi J, Yates MS, Wakabayashi N, Dolan PM, Aja S, et al. Role of Nrf2 in prevention of high-fat diet-induced obesity by synthetic triterpenoid CDDO-imidazolide. Eur J Pharmacol. 2009;620:138–44.

    Article  PubMed  CAS  Google Scholar 

  69. Tomobe K, Shinozuka T, Kuroiwa M, Nomura Y. Age-related changes of Nrf2 and phosphorylated GSK-3beta in a mouse model of accelerated aging (SAMP8). Arch Gerontol Geriatr. 2012;54:e1–7.

    Article  PubMed  CAS  Google Scholar 

  70. Ungvari Z, Bailey-Downs L, Gautam T, Sosnowska D, Wang M, Monticone RE, et al. Age-associated vascular oxidative stress, Nrf2 Dysfunction, and NF-κB activation in the nonhuman primate Macaca mulatta. J Gerontol A Biol Sci Med Sci. 2011;66:866–75.

    Article  PubMed  Google Scholar 

  71. Ungvari Z, Bailey-Downs L, Gautam T, Jimenez R, Losonczy G, Zhang C, et al. Adaptive induction of NF-E2-related factor-2-driven antioxidant genes in endothelial cells in response to hyperglycemia. Am J Physiol Heart Circ Physiol. 2011;300:H1133–40.

    Article  PubMed  CAS  Google Scholar 

  72. Collins AR, Lyon CJ, Xia X, Liu JZ, Tangirala RK, Yin F, et al. Age-accelerated atherosclerosis correlates with failure to upregulate antioxidant genes. Circ Res. 2009;104:e42–54.

    Article  PubMed  CAS  Google Scholar 

  73. Gupte AA, Liu JZ, Ren Y, Minze LJ, Wiles JR, Collins AR, et al. Rosiglitazone attenuates age- and diet-associated nonalcoholic steatohepatitis in male low-density lipoprotein receptor knockout mice. Hepatology. 2010;52:2001–11.

    Article  PubMed  CAS  Google Scholar 

  74. Meulener MC, Xu K, Thomson L, Ischiropoulos H, Bonini NM. Mutational analysis of DJ-1 in Drosophila implicates functional inactivation by oxidative damage and aging. Proc Natl Acad Sci U S A. 2006;103:12517–22.

    Article  PubMed  CAS  Google Scholar 

  75. Valcarcel-Ares MN, Gautam T, Warrington JP, Bailey-Downs L, Sosnowska D, de Cabo R, et al. Disruption of Nrf2 signaling impairs angiogenic capacity of endothelial cells: implications for microvascular aging. J Gerontol A Biol Sci Med Sci. 2012;67:821–9.

    Article  PubMed  Google Scholar 

  76. Zakkar M, Van der Heiden K, le Luong A, Chaudhury H, Cuhlmann S, Hamdulay SS, et al. Activation of Nrf2 in endothelial cells protects arteries from exhibiting a proinflammatory state. Arterioscler Thromb Vasc Biol. 2009;29:1851–7.

    Article  PubMed  CAS  Google Scholar 

  77. Hur KY, Kim SH, Choi MA, Williams DR, Lee YH, Kang SW, et al. Protective effects of magnesium lithospermate B against diabetic atherosclerosis via Nrf2-ARE-NQO1 transcriptional pathway. Atherosclerosis. 2010;211:69–76.

    Article  PubMed  CAS  Google Scholar 

  78. Pedrosa AM, Faine LA, Grosso DM, de Las Heras B, Bosca L, Abdalla DS. Electronegative LDL induction of apoptosis in macrophages: involvement of Nrf2. Biochim Biophys Acta. 1801;2010:430–7.

    Google Scholar 

  79. Sussan TE, Jun J, Thimmulappa R, Bedja D, Antero M, Gabrielson KL, et al. Disruption of Nrf2, a key inducer of antioxidant defenses, attenuates ApoE-mediated atherosclerosis in mice. PLoS One. 2008;3:e3791.

    Article  PubMed  Google Scholar 

  80. Barajas B, Che N, Yin F, Rowshanrad A, Orozco LD, Gong KW, et al. NF-E2-related factor 2 promotes atherosclerosis by effects on plasma lipoproteins and cholesterol transport that overshadow antioxidant protection. Arterioscler Thromb Vasc Biol. 2011;31:58–66.

    Article  PubMed  CAS  Google Scholar 

  81. Freigang S, Ampenberger F, Spohn G, Heer S, Shamshiev AT, Kisielow J, et al. Nrf2 is essential for cholesterol crystal-induced inflammasome activation and exacerbation of atherosclerosis. Eur J Immunol. 2011;41:2040–51.

    Article  PubMed  CAS  Google Scholar 

  82. Yang H, Roberts LJ, Shi MJ, Zhou LC, Ballard BR, Richardson A, et al. Retardation of atherosclerosis by overexpression of catalase or both Cu/Zn-superoxide dismutase and catalase in mice lacking apolipoprotein E. Circ Res. 2004;95:1075–81.

    Article  PubMed  CAS  Google Scholar 

  83. Hanley AJ, Williams K, Festa A, Wagenknecht LE, D'Agostino Jr RB, Kempf J, et al. Elevations in markers of liver injury and risk of type 2 diabetes: the insulin resistance atherosclerosis study. Diabetes. 2004;53:2623–32.

    Article  PubMed  CAS  Google Scholar 

  84. Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41:1313–21.

    Article  PubMed  Google Scholar 

  85. Begriche K, Igoudjil A, Pessayre D, Fromenty B. Mitochondrial dysfunction in NASH: causes, consequences and possible means to prevent it. Mitochondrion. 2006;6:1–28.

    Article  PubMed  CAS  Google Scholar 

  86. Nobili V, Pastore A, Gaeta LM, Tozzi G, Comparcola D, Sartorelli MR, et al. Glutathione metabolism and antioxidant enzymes in patients affected by nonalcoholic steatohepatitis. Clin Chim Acta. 2005;355:105–11.

    Article  PubMed  CAS  Google Scholar 

  87. Arias I, Wolkoff A, Boyer J, Shafritz D, Fausto N, Alter H, et al. The liver: biology and pathobiology. 5th ed. Hoboken NJ: Wiley-Blackwell publishing; 2009.

    Google Scholar 

  88. Okada K, Warabi E, Sugimoto H, Horie M, Gotoh N, Tokushige K, et al. Deletion of Nrf2 leads to rapid progression of steatohepatitis in mice fed atherogenic plus high-fat diet. J Gastroenterol. 2012. doi:10:1007/s00535-012-0659-z

  89. Sugimoto H, Okada K, Shoda J, Warabi E, Ishige K, Ueda T, 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. 2010;298:G283–94.

    Article  PubMed  CAS  Google Scholar 

  90. Choi HK, Pokharel YR, Lim SC, Han HK, Ryu CS, Kim SK, et al. Inhibition of liver fibrosis by solubilized coenzyme Q10: role of Nrf2 activation in inhibiting transforming growth factor-beta1 expression. Toxicol Appl Pharmacol. 2009;240:377–84.

    Article  PubMed  CAS  Google Scholar 

  91. Oh CJ, Kim JY, Min AK, Park KG, Harris RA, Kim HJ, et al. Sulforaphane attenuates hepatic fibrosis via NF-E2-related factor 2-mediated inhibition of transforming growth factor-beta/Smad signaling. Free Radic Biol Med. 2012;52:671–82.

    Article  PubMed  CAS  Google Scholar 

  92. Wu KC, Zhang Y, Klaassen CD. Nrf2 protects against diquat-induced liver and lung injury. Free Radic Res. 2012;46:1220–9.

    Article  PubMed  CAS  Google Scholar 

  93. Jaeschke H, Woolbright BL. Current strategies to minimize hepatic ischemia-reperfusion injury by targeting reactive oxygen species. Transplant Rev. 2012;26:103–14.

    Article  Google Scholar 

  94. Kurzawski M, Dziedziejko V, Urasinska E, Post M, Wojcicki M, Mietkiewski J, et al. Nuclear factor erythroid 2-like 2 (Nrf2) expression in end-stage liver disease. Environ Toxicol Pharmacol. 2012;34:87–95.

    Article  PubMed  CAS  Google Scholar 

  95. Chitturi S, Abeygunasekera S, Farrell GC, Holmes-Walker J, Hui JM, Fung C, et al. NASH and insulin resistance: Insulin hypersecretion and specific association with the insulin resistance syndrome. Hepatology. 2002;35:373–9.

    Article  PubMed  CAS  Google Scholar 

  96. Marchesini G, Bugianesi E, Forlani G, Cerrelli F, Lenzi M, Manini R, et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology. 2003;37:917–23.

    Article  PubMed  Google Scholar 

  97. Angulo P, Keach JC, Batts KP, Lindor KD. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology. 1999;30:1356–62.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors express thanks to the MacDonald Foundation for a generous grant to WAH and the American Heart Association (12POST9020018 to AAG) for support of this work.

Conflict of Interest

Anisha A. Gupte declares that she has no conflict of interest.

Christopher J. Lyon declares that he has no conflict of interest.

Willa A. Hsueh has received honoraria, and travel/accommodations expenses covered or reimbursed, from Merck for speaker presentations.

Author information

Authors and Affiliations

  1. The Methodist Diabetes and Metabolism Institute, Center for Diabetes Research in The Methodist Hospital Research Institute, Weill Cornell Medical College, R8-111, 6670 Bertner Ave, Houston, 77030, TX, USA

    Anisha A. Gupte, Christopher J. Lyon & Willa A. Hsueh

Authors
  1. Anisha A. Gupte
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christopher J. Lyon
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Willa A. Hsueh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Willa A. Hsueh.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gupte, A.A., Lyon, C.J. & Hsueh, W.A. Nuclear Factor (Erythroid-Derived 2)-Like-2 Factor (Nrf2), a Key Regulator of the Antioxidant Response to Protect Against Atherosclerosis and Nonalcoholic Steatohepatitis. Curr Diab Rep 13, 362–371 (2013). https://doi.org/10.1007/s11892-013-0372-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11892-013-0372-1

Keywords

Search

Navigation