The role of reactive oxygen species in adipocytes and obesity: with special reference to extracellular SOD

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Extracellular superoxide dismutase (EC-SOD) is a copper- and zinc-containing secretary glycoprotein, located in extracellular fluids including plasma and the extracellular matrix of tissues. The primary structure of EC-SOD indicates that the enzyme consists of an N-terminal hydrophobic signal peptide for secretion, a Cu, Zn-SOD-like domain in the middle portion, and a heparin-binding region, which contains clusters of positively charged amino acids in the C-terminal portion, as well as one potential site for N-linked gycosylation. Histochemical examination of mouse tissues showed nuclear staining of EC-SOD, and the nuclear translocation of EC-SOD was also confirmed in cultured cells. The EC-SOD which wa secreted into the medium was incorporated into 3T3-L1 preadipocytes and a significant fraction of the material taken up was localized in the mucleus. Site-directed mutagenesis indicated that the heparin-binding domain of EC-SOD functions as the nuclear localization signal. Moreover, EC-SOD was incorporated from conditioned medium of stable EC-SOD expressing CHO-EK cells into 3T3-L1 cells within 15 min. The uptake was clearly inhibited by the addition of heparin at a concentration of 0.4 μg/ml. Nuclear translocation of the incorporated EC-SOD was markedly enhanced by H_2O_2 treatment following incubation with the CHO-EK medium. The results obtained here suggest that the upregulation of the nuclear translocation of EC-SOD by oxidative stress might play a role in the mechanism by which the nucleus is protected against oxidative damage of genomic DNA, possibly leading to a low incidence of lifestyle related diseases such as cancer.