Rhiannon Hardwick - DIVERSITY IN ANTIOXIDANT RESPONSE ENZYMES IN PROGRESSIVE STAGES OF HUMAN NON-ALCOHOLIC FATTY LIVER DISEASE.

Version 1

      Publication Details (including relevant citation   information):

      Drug Metabolism and Disposition

      Epub ahead of print

      2010, Aug 30

      PMID: 20805291

      Abstract:

      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.

      Address (URL): http://dmd.aspetjournals.org/content/early/2010/08/30/dmd.110.035006.long