Diversity in antioxidant response enzymes in progressive stages of human nonalcoholic fatty liver disease.
Nonalcoholic fatty liver disease (NAFLD), which occurs in approximately 17 to 40% of Americans, encompasses progressive stages of liver damage ranging from steatosis to nonalcoholic steatohepatitis (NASH). Inflammation and oxidative stress are known characteristics of NAFLD; however, the precise mechanisms occurring during disease progression remain unclear. The purpose of the current study was to determine whether the expression or function of enzymes involved in the antioxidant response, NAD(P)H:quinone oxidoreductase 1 (NQO1), glutathione transferase (GST), and glutamate cysteine ligase, are altered in the progression of human NAFLD. Human livers staged as normal, steatotic, NASH (fatty), and NASH (not fatty) were obtained from the Liver Tissue Cell Distribution System. NQO1 mRNA, protein, and activity tended to increase with disease progression. mRNA levels of the GST isoforms A1, A2, A4, M3, and P1 increased with NAFLD progression. Likewise, GST A and P protein increased with progression; however, GST M protein levels tended to decrease. Of interest, total GST activity toward the substrate 1-chloro-2,4-dinitrobenzene decreased with NAFLD progression. GSH synthesis does not seem to be significantly dysregulated in NAFLD progression; however, the GSH/oxidized glutathione redox ratio seemed to be reduced with disease severity, indicating the presence of oxidative stress and depletion of GSH throughout progression of NAFLD. Malondialdehyde concentrations were significantly increased with disease progression, further indicating the presence of oxidative stress. Nuclear immunohistochemical staining of nuclear factor E2-related factor 2 (Nrf2), an indicator of activation of the transcription factor, was evident in all stages of NAFLD. The current data suggest that Nrf2 activation occurs in response to disease progression followed by induction of specific Nrf2 targets, whereas functionality of specific antioxidant defense enzymes seems to be impaired as NAFLD progresses.
Hardwick
Rhiannon N
RN
Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona, USA.
Fisher
Craig D
CD
Canet
Mark J
MJ
Lake
April D
AD
Cherrington
Nathan J
NJ
D000328:Adult; D000975:Antioxidants / Q000378:metabolism*; D018450:Disease Progression; D005234:Fatty Liver / Q000201:enzymology* / Q000473:pathology; D005721:Glutamate-Cysteine Ligase / Q000032:analysis / Q000235:genetics; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000032:analysis / Q000235:genetics; D006801:Humans; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000032:analysis / Q000235:genetics; D051267:NF-E2-Related Factor 2 / Q000378:metabolism
D000975:Antioxidants; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D005982:Glutathione Transferase; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione
J Biol Chem. 2000 May 19;275(20):15466-73
10747902
N Engl J Med. 2002 Apr 18;346(16):1221-31
11961152
Clin Chim Acta. 2003 Jul 1;333(1):19-39
12809732
Chem Biol Interact. 1998 Apr 24;111-112:377-88
9679568
Arch Toxicol. 2008 Dec;82(12):959-64
18488193
Drug Metab Pharmacokinet. 2006 Dec;21(6):437-57
17220560
Cancer Lett. 2004 Jun 25;209(2):155-63
15159017
Curr Protoc Toxicol. 2001;Chapter 6:Unit6.4
23045056
Mol Cell Proteomics. 2009 Apr;8(4):670-80
19054759
J Clin Gastroenterol. 2006 Mar;40 Suppl 1:S17-29
16540762
Pharmacogenomics. 2009 Jan;10(1):29-34
19102712
Annu Rev Pharmacol Toxicol. 2005;45:51-88
15822171
Acta Biochim Pol. 2006;53(1):237-42
16404476
Ann Epidemiol. 2007 Nov;17(11):863-9
17728149
Hepatology. 2005 Jun;41(6):1313-21
15915461
World J Gastroenterol. 2006 Mar 28;12(12):1937-40
16610002
Drug Metab Rev. 2006;38(4):769-89
17145701
Biochem Biophys Res Commun. 1997 Jul 18;236(2):313-22
9240432
Methods Enzymol. 2005;401:9-42
16399377
Biochem Biophys Res Commun. 2007 Jun 8;357(3):575-8
17434454
Trends Mol Med. 2008 Feb;14(2):72-81
18218340
Methods Enzymol. 2004;382:115-44
15047100
Toxicology. 2007 Feb 12;230(2-3):197-206
17188792
J Toxicol Sci. 2007 Dec;32(5):453-68
18198478
Toxicol Pathol. 2007 Jun;35(4):459-73
17562481
J Am Soc Nephrol. 2009 Feb;20(2):405-15
19056870
Mutat Res. 2009 Mar 31;674(1-2):93-100
18950733
J Biochem Mol Toxicol. 2007;21(4):216-20
17721935
Free Radic Biol Med. 2000 Aug;29(3-4):254-62
11035254
Cell Stress Chaperones. 2006 Winter;11(4):356-63
17278884
Chem Biol Interact. 1997 Dec 12;108(1-2):67-78
9463521
Mol Aspects Med. 2009 Feb-Apr;30(1-2):42-59
18601945
Free Radic Biol Med. 2004 May 15;36(10):1199-207
15110384
Ann Med. 2009;41(4):265-78
19353360
Methods Enzymol. 2004;382:355-64
15047111
Drug Metab Dispos. 2009 Oct;37(10):2087-94
19651758
Methods Enzymol. 2005;401:116-35
16399382