Publication Details (including relevant citation information):
Drug Metabolism and Disposition
Epub ahead of print
2010, Aug 30
Non-alcoholic fatty liver disease (NAFLD), which occurs in approximately 17-40% of Americans, encompasses progressive stages of liver damage ranging from steatosis to non-alcoholic 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, glutathione S-transferase, 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. Similarly, GST A and P protein increased with progression; however GST M protein levels tended to decrease. Interestingly, total GST activity toward the substrate CDNB decreased with NAFLD progression. GSH synthesis does not appear to be significantly dysregulated in NAFLD progression; however, the GSH:GSSG redox ratio appeared to be reduced with disease severity, indicating the presence of oxidative stress and depletion of GSH throughout progression of NAFLD. MDA concentrations were significantly increased with disease progression, further indicating the presence of oxidative stress. Nuclear immunohistochemical staining of 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, while functionality of specific antioxidant defense enzymes appear to be impaired as NAFLD progresses.