Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Current Diabetes Reports
Published in: Current Diabetes Reports 3/2013

01-06-2013 | Macrovascular Complications in Diabetes (PD Reaven, Section Editor)

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

Authors: Anisha A. Gupte, Christopher J. Lyon, Willa A. Hsueh

Published in: Current Diabetes Reports | Issue 3/2013

Login to get access

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.
Literature
1.
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
5.
Shimada M, Hashimoto E, Kaneda H, Noguchi S, Hayashi N. Nonalcoholic steatohepatitis: risk factors for liver fibrosis. Hepatol Res. 2002;24:429–38.PubMedCrossRef
6.
Schrauwen P, Hesselink MK. Oxidative capacity, lipotoxicity, and mitochondrial damage in type 2 diabetes. Diabetes. 2004;53:1412–7.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
13.
Gugliucci A. Glycation as the glucose link to diabetic complications. J Am Osteopath Assoc. 2000;100:621–34.PubMed
14.
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.
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.PubMedCrossRef
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.PubMedCrossRef
18.
Geraldes P, King GL. Activation of protein kinase C isoforms and its impact on diabetic complications. Circ Res. 2010;106:1319–31.PubMedCrossRef
19.
King GL, Loeken MR. Hyperglycemia-induced oxidative stress in diabetic complications. Histochem Cell Biol. 2004;122:333–8.PubMedCrossRef
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.PubMedCrossRef
21.
Forstermann U. Nitric oxide and oxidative stress in vascular disease. Pflugers Arch. 2010;459:923–39.PubMedCrossRef
22.
Hsueh WA, Lyon CJ, Quinones MJ. Insulin resistance and the endothelium. Am J Med. 2004;117:109–17.PubMedCrossRef
23.
Kalupahana NS, Moustaid-Moussa N. The renin-angiotensin system: a link between obesity, inflammation and insulin resistance. Obes Rev. 2012;13:136–49.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.
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. PubMedCrossRef
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.PubMedCrossRef
29.
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
33.
Forman HJ, Maiorino M, Ursini F. Signaling functions of reactive oxygen species. Biochemistry. 2010;49:835–42.
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
41.
Milic S, Stimac D. Nonalcoholic fatty liver disease/steatohepatitis: epidemiology, pathogenesis, clinical presentation and treatment. Dig Dis. 2012;30:158–62.PubMedCrossRef
42.
Malaguarnera M, Di Rosa M, Nicoletti F, Malaguarnera L. Molecular mechanisms involved in NAFLD progression. J Mol Med. 2009;87:679–95.PubMedCrossRef
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. PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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. PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
92.
Wu KC, Zhang Y, Klaassen CD. Nrf2 protects against diquat-induced liver and lung injury. Free Radic Res. 2012;46:1220–9.PubMedCrossRef
93.
Jaeschke H, Woolbright BL. Current strategies to minimize hepatic ischemia-reperfusion injury by targeting reactive oxygen species. Transplant Rev. 2012;26:103–14.CrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
97.
Angulo P, Keach JC, Batts KP, Lindor KD. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology. 1999;30:1356–62.PubMedCrossRef
Metadata
Title
Nuclear Factor (Erythroid-Derived 2)-Like-2 Factor (Nrf2), a Key Regulator of the Antioxidant Response to Protect Against Atherosclerosis and Nonalcoholic Steatohepatitis
Authors
Anisha A. Gupte
Christopher J. Lyon
Willa A. Hsueh
Publication date
01-06-2013
Publisher
Current Science Inc.
Published in
Current Diabetes Reports / Issue 3/2013
Print ISSN: 1534-4827
Electronic ISSN: 1539-0829
DOI
https://doi.org/10.1007/s11892-013-0372-1

Other articles of this Issue 3/2013

Current Diabetes Reports 3/2013 Go to the issue

Macrovascular Complications in Diabetes (PD Reaven, Section Editor)

Do Statins Cause Diabetes?

Diabetes and Other Diseases—Emerging Associations (D Aron, Section Editor)

Diabetes and Infections-Hepatitis C: Is There Type 2 Diabetes Excess in Hepatitis C Infection?

Macrovascular Complications in Diabetes (PD Reaven, Section Editor)

Is the Risk and Nature of CVD the Same in Type 1 and Type 2 Diabetes?

Pharmacologic Treatment of Type 2 Diabetes and Obesity (A Vella, Section Editor)

The Future of Thiazolidinedione Therapy in the Management of Type 2 Diabetes Mellitus

Macrovascular Complications in Diabetes (PD Reaven, Section Editor)

Exercise and Diabetes-Related Cardiovascular Disease: Systematic Review of Published Evidence from Observational Studies and Clinical Trials

Diabetes and Other Diseases—Emerging Associations (D Aron, Section Editor)

Diabetes and HIV: Current Understanding and Future Perspectives
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits