TI - TRbeta deficiency decreases ADMA content in regenerating live . AB - A possible explanation for the increased apoptosis in the regenerating liver of TR KO mice is an enhanced oxidative and nitrosative stress . To evaluate oxidative stress , we measured the levels of 8-oxo-deoxyguanosine ( 8-oxo-dG ) , malondialdehyde ( MDA ) and GSH-GSSG , and the activity of glutathione peroxidase ( GPx ) . Neither TRbeta KO or TRalpha1/TRbeta double KO mice showed significant variation in these parameters compared with WT animals , and only a tendency of low statistical significance to higher levels of GSH and lower of 8-oxo-dG was evidenced in the KO model ( Fig 5A ) . However , the liver content of nitrotyrosine was elevated in the KO animals ( Fig 5B ) , indicating enhanced nitrosative stress . TRalpha1/TRbeta gene deficiency did not affect the protein expression level or phosphorylaTION state of NOS-3 , suggesting that the activity of this isoenzyme was not regulated by changes in the PHOSphorylation of the specific Ser473 residue ; however , the characteristic transient spike in NOS-2 expression in regenerating liver [22] was significantly enhanced ( Fig 5C ) . Other enzymes induced in regenerating liver , such as glutathione-S-transferase ( GST ) , showed similar profiles in WT and KO mice ( Fig 5C ) . The enhanced nitrosative stress in TRalpha1/TRbeta double KO mice suggested higher NOS activity . Consistently , serum levels of ADMA -a physiological NOS inhibitor [15] , [16] , [23] , [24] - were specifically decreased in TRbeta KO and TRalpha1/TRbeta double KO mice 24-48 h after PH , with the start of recovery evident at 72 h ( Fig 6A ) . This ADMA decrease was accompanied by increased expression and activity of DDAH-1 , which converts ADMA into citrulline ( Fig 6B ) . One candidate regulator of DDAH-I expression in liver is the nuclear receptor FXR [25] , and the FXR content of liver nuclear extracts was much higher in the TRalpha1/TRbeta double KO than in the WT animals ( Fig 6C ) . Likewise , mRNA expression of FXR and the bile salt export pump ( mBSEP ) , a target of FXR activity [26] , [27] , were always higher in the TRalpha1/TRbeta double KO mice than in the WT group , suggesting a higher activity of FXR in these animals after PH (Fig 6D) . Moreover , whereas FXR mRNA and protein expression showed a decrease at 24 h PH in WT animals , an increase was observed in the TRalpha1/TRbeta double KO group . These differential changes in FXR expression might explain the comparatively high expression of DDAH-1 in the regenerating livers of TRalpha1/TRbeta double KO mice ( Fig 6B ) .