Administration Of Ppar Beta/Delta Agonist Reduces Copper-Induced Liver Damage In Mice: Possible Implications In Clinical Practice

In this study we investigated if peroxisome proliferator-activated receptor beta/delta activation protects from copper-induced acute liver damage. Mice treated with copper had significant body weight loss, serum alanine aminotransferase increase, modest changes in liver histology, increase of tumor necrosis factor alpha and macrophage inflammatory protein 2 mRNA and 8-hydroxy-2'-deoxyguanosine. Mice treated with copper and peroxisome proliferator-activated receptor beta/delta agonist GW0742 had significantly less body weight loss, less serum alanine aminotransferase increase, less tumor necrosis factor alpha, macrophage inflammatory protein-2 and 8-hydroxy-2'-deoxyguanosine upregulation than copper treated mice. The opposite effect was observed in mice treated with copper and peroxisome proliferator-activated receptor beta/delta antagonist G5K0660. In vitro, copper induced reactive oxygen species, which was lower in cells treated with GW0742 or transfected with peroxisome proliferator-activated receptor beta/delta expression vector; together, transfection and GW0742 had an additive reactive oxygen species-reducing effect. Copper also upregulated Fas ligand and Caspase 3/7 activity, effects that were significantly lower in cells also treated with GW0742. In conclusion, peroxisome proliferatoractivated receptor beta/delta activation reduced copper-induced reactive oxygen species, pro-inflammatory and acute phase reaction cytokines in mice liver. Peroxisome proliferator-activated receptor beta/delta agonists could become useful in the management of copper-induced liver damage.