Diversity in Antioxidant Response Enzymes in Progressive Stages of Human Nonalcoholic Fatty Liver Disease

• Published in: Drug metabolism and disposition Vol. 38; no. 12; pp. 2293 - 2301
• Main Authors: Hardwick, Rhiannon N., Fisher, Craig D., Canet, Mark J., Lake, April D., Cherrington, Nathan J.
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Elsevier Inc 01.12.2010; American Society for Pharmacology and Experimental Therapeutics; The American Society for Pharmacology and Experimental Therapeutics
• Subjects: Adult; Antioxidants - metabolism; Biological and medical sciences; Disease Progression; Fatty Liver - enzymology; Fatty Liver - pathology; Gastroenterology. Liver. Pancreas. Abdomen; Glutamate-Cysteine Ligase - analysis; Glutamate-Cysteine Ligase - genetics; Glutathione - metabolism; Glutathione Transferase - analysis; Glutathione Transferase - genetics; Humans; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Medical sciences; NAD(P)H Dehydrogenase (Quinone) - analysis; NAD(P)H Dehydrogenase (Quinone) - genetics; NF-E2-Related Factor 2 - metabolism; Other diseases. Semiology; Pharmacology. Drug treatments; NQO1; GSSG; NAFLD; DAB; DCPIP; GST; CDNB; TBARS; MDA; NASH; GCL; GCLC; ARE; Nrf2; ROS; GCLM; HNE; ERK; Human; Clinical stage; Enzyme; Non alcoholic steatohepatitis; Digestive diseases; Hepatic disease; Antioxidant
• DOI: 10.1124/dmd.110.035006
• ISSN: 0090-9556; 1521-009X

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.