Activation of the Nrf2-ARE pathway in hepatocytes protects against steatosis in nutritionally induced non-alcoholic steatohepatitis in mice

Toxicological Sciences

Volumn 142, Issue 2, 2014, Pages 361-374

  Lee, Lung Yi ^a   Köhler, Ulrike A ^b   Zhang, Li ^a   Roenneburg, Drew ^a   Werner, Sabine ^b   Johnson, Jeffrey A ^c,d   Foley, David P ^a,e  

^a UNIVERSITY OF WISCONSIN SCHOOL OF MEDICINE AND PUBLIC HEALTH   (United States)

^b ETH ZURICH   (Switzerland)

^c UNIVERSITY OF WISCONSIN MADISON   (United States)

^d UNIVERSITY OF WISCONSIN MADISON   (United States)

^e WILLIAM S MIDDLETON MEMORIAL VETERANS HOSPITAL   (United States)

Author keywords

Antioxidants; Liver; NASH; Nrf2; Steatosis; Transgenic mice

Indexed keywords

8 ISOPROSTANE; ALPHA SMOOTH MUSCLE ACTIN; AMINOTRANSFERASE; CHOLINE; GAMMA INTERFERON INDUCIBLE PROTEIN 10; GELATINASE A; GELATINASE B; GLUTAMATE CYSTEINE LIGASE; GLUTATHIONE TRANSFERASE A2; GLUTATHIONE TRANSFERASE A4; GLUTATHIONE TRANSFERASE M1; INTERLEUKIN 12P40; INTERLEUKIN 1BETA; INTERLEUKIN 6; LIPID; LOW DENSITY LIPOPROTEIN CHOLESTEROL; METHIONINE; MONOCYTE CHEMOTACTIC PROTEIN 1; TISSUE INHIBITOR OF METALLOPROTEINASE 1; TISSUE INHIBITOR OF METALLOPROTEINASE 2; TOLL LIKE RECEPTOR ADAPTOR MOLECULE 1; TRANSCRIPTION FACTOR NRF2; TRIACYLGLYCEROL; TUMOR NECROSIS FACTOR; NFE2L2 PROTEIN, MOUSE;

AMINOTRANSFERASE BLOOD LEVEL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTIOXIDANT RESPONSIVE ELEMENT; ARTICLE; CELL ACTIVATION; CLINICAL ASSESSMENT; COMPARATIVE STUDY; CONTROLLED STUDY; DIET SUPPLEMENTATION; DIETARY INTAKE; DISEASE COURSE; ENZYME ACTIVATION; FATTY ACID OXIDATION; FATTY LIVER; FEEDING; GENE EXPRESSION; HEPATITIS; LIPID METABOLISM; LIVER CELL DAMAGE; LIVER PROTECTION; METHIONINE CHOLINE DEFICIENT DIET; NONALCOHOLIC FATTY LIVER; NONHUMAN; OXIDATIVE STRESS; PROTEIN EXPRESSION; SIGNAL TRANSDUCTION; STELLATE CELL; TRANSGENIC MOUSE; ANIMAL; DIET; GENETICS; IMMUNOHISTOCHEMISTRY; LIVER CELL; LIVER FUNCTION TEST; METABOLISM; NON-ALCOHOLIC FATTY LIVER DISEASE; PATHOLOGY; PHYSIOLOGY; PROMOTER REGION; WESTERN BLOTTING;

ANIMALIA; MUS; MUS MUSCULUS; RODENTIA;

ANIMALS; ANTIOXIDANT RESPONSE ELEMENTS; BLOTTING, WESTERN; DIET; GENE EXPRESSION; HEPATOCYTES; IMMUNOHISTOCHEMISTRY; LIPID METABOLISM; LIVER FUNCTION TESTS; MICE, TRANSGENIC; NF-E2-RELATED FACTOR 2; NON-ALCOHOLIC FATTY LIVER DISEASE; OXIDATIVE STRESS; PROMOTER REGIONS, GENETIC; SIGNAL TRANSDUCTION; TRIGLYCERIDES;

EID: 84922463623     PISSN: 10966080     EISSN: 10960929     Source Type: Journal    
DOI: 10.1093/toxsci/kfu184     Document Type: Article

References (37)

1. Adams, L. A., and Lindor, K. D. (2007). Nonalcoholic fatty liver disease. Ann. Epidemiol. 17, 863-869.
2. Akpolat, N., Yahsi, S., Godekmerdan, A., Yalniz, M., and Demirbag, K. (2005). The value of alpha-SMA in the evaluation of hepatic fibrosis severity in hepatitis B infection and cirrhosis development: a histopathological and immunohistochemical study. Histopathology 47, 276-280.
3. Aleksunes, L. M., and Klaassen, C. D. (2012). Coordinated regulation of hepatic phase I and II drug-metabolizing genes and transporters using AhR-, CAR-, PXR-, PPARalpha-, and Nrf2-null mice. Drug Metabolism and Disposition: The Biological Fate of Chemicals 40, 1366-1379.
4. Armstrong, D., and Browne, R. (1994). The analysis of free radicals, lipid peroxides, antioxidant enzymes and compounds related to oxidative stress as applied to the clinical chemistry laboratory. Adv Exp Med Biol. 366, 43-58.
5. Benyon, R. C., Iredale, J. P., Goddard, S., Winwood, P. J., and Arthur, M. J. (1996). Expression of tissue inhibitor of metalloproteinases 1 and 2 is increased in fibrotic human liver. Gastroenterology 110, 821-831.
6. Blasiole, D. A., Davis, R. A., and Attie, A. D. (2007). The physiological and molecular regulation of lipoprotein assembly and secretion. Mol. Biosyst. 3, 608-619.
7. Caballero, F., Fernandez, A., Matias, N., Martinez, L., Fucho, R., Elena, M., Caballeria, J., Morales, A., Fernandez-Checa, J. C., and Garcia-Ruiz, C. (2010). Specific contribution of methionine and choline in nutritional nonalcoholic steatohepatitis: impact on mitochondrial S-adenosyl-L-methionine and glutathione. J. Biol. Chem. 285, 18528-18536.
8. Carpino, G., Morini, S., Ginanni Corradini, S., Franchitto, A., Merli, M., Siciliano, M., Gentili, F., Onetti Muda, A., Berloco, P., Rossi, M., et al. (2005). Alpha-SMA expression in hepatic stellate cells and quantitative analysis of hepatic fibrosis in cirrhosis and in recurrent chronic hepatitis after liver transplantation. Dig. Liver Dis. 37, 349-356.
9. Chowdhry, S., Nazmy, M. H., Meakin, P. J., Dinkova-Kostova, A. T., Walsh, S. V., Tsujita, T., Dillon, J. F., Ashford, M. L., and Hayes, J. D. (2010). Loss of Nrf2 markedly exacerbates nonalcoholic steatohepatitis. Free Radic. Biol. Med. 48, 357-371.
10. Farrell, G. C., and Larter, C. Z. (2006). Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology 43(Suppl. 1), S99-S112.
11. Flegal, K. M., Carroll, M. D., Kit, B. K., and Ogden, C. L. (2012). Prevalence of obesity and trends in the distribution of body mass index among US adults, 1999-2010. JAMA 307, 491-497.
12. Folch, J., Lees, M., and Sloane Stanley, G. H. (1957). A simple method for the isolation and purification of total lipides from animal tissues. J. Biol. Chem. 226, 497-509.
13. Friedman, J. M., and Halaas, J. L. (1998). Leptin and the regulation of body weight in mammals. Nature 395, 763-770.
14. Kohler, U. A., Kurinna, S., Schwitter, D., Marti, A., Schafer, M., Hellerbrand, C., Speicher, T., and Werner, S. (2014). Activated Nrf2 impairs liver regeneration in mice by activation of genes involved in cell cycle control and apoptosis. Hepatology 60, 670-678.
15. Larter, C. Z., and Yeh, M. M. (2008). Animal models of NASH: getting both pathology and metabolic context right. J. Gastroenterol. Hepatol. 23, 1635-1648.
16. Lee, J. M., Calkins, M. J., Chan, K., Kan, Y. W., and Johnson, J. A. (2003). Identification of the NF-E2-related factor-2-dependent genes conferring protection against oxidative stress in primary cortical astrocytes using oligonucleotide microarray analysis. J. Biol. Chem. 278, 12029-12038.
17. More, V. R., Xu, J., Shimpi, P. C., Belgrave, C., Luyendyk, J. P., Yamamoto, M., and Slitt, A. L. (2013). Keap1 knockdown increases markers of metabolic syndrome after long-term high fat diet feeding. Free Radic. Biol. Med. 61C, 85-94.
18. Morrow, J. D., and Roberts, L. J., 2nd (1996). The isoprostanes. Current knowledge and directions for future research. Biochem. Pharmacol 51, 1-9.
19. Okada, K., Warabi, E., Sugimoto, H., Horie, M., Gotoh, N., Tokushige, K., Hashimoto, E., Utsunomiya, H., Takahashi, H., Ishii, T., et al. (2013). Deletion of Nrf2 leads to rapid progression of steatohepatitis in mice fed atherogenic plus high-fat diet. J. Gastroenterol. 48, 620-632.
20. Rasband, W. S. (1997-2012). ImageJ. Available at: http://imagej.nih.gov/ij/. Accessed October 23, 2012.
21. Rinella, M. E., Elias, M. S., Smolak, R. R., Fu, T., Borensztajn, J., and Green, R. M. (2008). Mechanisms of hepatic steatosis in mice fed a lipogenic methionine choline-deficient diet. J. Lipid Res. 49, 1068-1076.
22. Rockey, D. C., Boyles, J. K., Gabbiani, G., and Friedman, S. L. (1992). Rat hepatic lipocytes express smooth muscle actin upon activation in vivo and in culture. J. Submicrosc. Cytol. Pathol. 24, 193-203.
23. Rolo, A. P., Teodoro, J. S., and Palmeira, C. M. (2012). Role of oxidative stress in the pathogenesis of nonalcoholic steatohepatitis. Free Radic. Biol. Med. 52, 59-69.
24. Schafer, M., Farwanah, H., Willrodt, A. H., Huebner, A. J., Sandhoff, K., Roop, D., Hohl, D., Bloch, W., and Werner, S. (2012). Nrf2 links epidermal barrier function with antioxidant defense. EMBO Mol. Med. 4, 364-379.
25. Shin, S., Wakabayashi, J., Yates, M. S., Wakabayashi, N., Dolan, P. M., Aja, S., Liby, K. T., Sporn, M. B., Yamamoto, M., and Kensler, T. W. (2009). Role of Nrf2 in prevention of high-fat diet-induced obesity by synthetic triterpenoid CDDO-imidazolide. Eur. J. Pharmacol. 620, 138-144.
26. Spandidos, A., Wang, X., Wang, H., and Seed, B. (2010). PrimerBank: a resource of human and mouse PCR primer pairs for gene expression detection and quantification. Nucleic Acids Res. 38(Database issue), D792-D799.
27. Sugimoto, H., Okada, K., Shoda, J., Warabi, E., Ishige, K., Ueda, T., Taguchi, K., Yanagawa, T., Nakahara, A., Hyodo, I., et al. (2010). 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.
28. Taguchi, K., Fujikawa, N., Komatsu, M., Ishii, T., Unno, M., Akaike, T., Motohashi, H., and Yamamoto, M. (2012). Keap1 degradation by autophagy for the maintenance of redox homeostasis. Proc. Natl Acad. Sci. U. S. A. 109, 13561-13566.
29. Taguchi, K., Maher, J. M., Suzuki, T., Kawatani, Y., Motohashi, H., and Yamamoto, M. (2010). Genetic analysis of cytoprotective functions supported by graded expression of Keap1. Mol. Cell. Biol. 30, 3016-3026.
30. Tanaka, Y., Aleksunes, L. M., Yeager, R. L., Gyamfi, M. A., Esterly, N., Guo, G. L., and Klaassen, C. D. (2008). NF-E2-related factor 2 inhibits lipid accumulation and oxidative stress in mice fed a high-fat diet. J. Pharmacol. Exp. Ther. 325, 655-664.
31. Tanaka, Y., Ikeda, T., Yamamoto, K., Ogawa, H., and Kamisako, T. (2012). Dysregulated expression of fatty acid oxidation enzymes and iron-regulatory genes in livers of Nrf2-null mice. J. Gastroenterol. Hepatol. 27, 1711-1717.
32. Thurlby, P. L., and Trayhurn, P. (1978). The development of obesity in preweaning obob mice. Br. J. Nutr. 39, 397-402.
33. Wakabayashi, N., Dinkova-Kostova, A. T., Holtzclaw, W. D., Kang, M. I., Kobayashi, A., Yamamoto, M., Kensler, T. W., and Talalay, P. (2004). Protection against electrophile and oxidant stress by induction of the phase 2 response: fate of cysteines of the Keap1 sensor modified by inducers. Proc. Natl Acad. Sci. U. S. A. 101, 2040-2045.
34. Wang, Y., McLeod, R. S., and Yao, Z. (1997). Normal activity of microsomal triglyceride transfer protein is required for the oleate-induced secretion of very low density lipoproteins containing apolipoprotein B from McA-RH7777 cells. J. Biol. Chem. 272, 12272-12278.
35. Xu, J., Kulkarni, S. R., Donepudi, A. C., More, V. R., and Slitt, A. L. (2012). Enhanced Nrf2 activity worsens insulin resistance, impairs lipid accumulation in adipose tissue, and increases hepatic steatosis in leptin-deficient mice. Diabetes 61, 3208-3218.
36. Zhang, D. D., and Hannink, M. (2003). Distinct cysteine residues in Keap1 are required for Keap1-dependent ubiquitination of Nrf2 and for stabilization of Nrf2 by chemopreventive agents and oxidative stress. Mol. Cell. Biol. 23, 8137-8151.
37. Zhang, Y. K., Yeager, R. L., Tanaka, Y., and Klaassen, C. D. (2010). Enhanced expression of Nrf2 in mice attenuates the fatty liver produced by a methionine-and choline-deficient diet. Toxicol. Appl. Pharmacol. 245, 326-334.