Effect of long-term treatment with trivalent chromium on erythropoietin production in HepG2 cells

Trivalent chromium (Cr(III)) is sometimes taken as a long-term supplement, but its effectiveness is unclear. Recently, Cr(III) reportedly modulates peroxisome proliferator-activated receptor gamma (PPAR gamma) expression. Our previous study reported that increased PPAR gamma after 24 h Cr(III) treatment promoted erythropoietin (EPO) production in HepG2 cells. In the current study, we analyzed 4-week Cr(III) treatment effects on PPAR gamma and EPO production in HepG2 cells. Long-term Cr(III) treatment resulted in significantly elevated mRNA expression levels of PPAR gamma and EPO compared to controls. Additionally, treatment with a PPAR gamma inhibitor suppressed EPO mRNA expression. Increased EPO mRNA expression due to stimulation with hypoxia or cobalt was unaffected by longterm Cr(III) treatment. Administration of lipopolysaccharide and pyocyanin which causes oxidative stress, promoted EPO production, but this effect was attenuated in cells treated with Cr(III). Long-term Cr(III) treatment increased hypoxia inducible factor (HIF)-1 alpha and 2 alpha mRNA expression and protein levels. Increased PPAR gamma, induced by long-term Cr(III) treatment, suppressed sirtuin1 (SIRT1) mRNA expression and increased EPO mRNA expression, suggesting that increased PPAR gamma attenuated the suppressive effect of SIRT1 on HIF. These results suggest that the sustained increase in PPAR gamma during long-term Cr(III) treatment maintains increased EPO production through a mechanism different from that observed under hypoxia.