Identification of Peroxisome Proliferator-Activated Receptors as Novel Regulators of Bovine Hepcidin Expression

Hepcidin centrally regulates systemic iron status. We previously revealed that activities of trans-factor to induce hepcidin expression are distinct between cattle and humans/mice in which regulation of hepcidin expression is well-examined. Here we characterized the cis-element of the bovine hepcidin promoter. Bovine hepcidin transcription was stimulated by co-expression of peroxisome proliferator-activated receptor (PPAR) and retinoid X receptor (RXR) by a stimulus screening for regulator of transcription. PPARα and PPARγ, lipid metabolism-related transcription factors, cooperatively increased expression of bovine hepcidin reporter with RXR in a synthetic agonist-independent manner. PPARα is predominantly expressed in the liver, and down-regulation of PPARα expression decreased hepcidin mRNA levels in bovine hepatocytes. The PPAR-response element (PPRE) that is responsible for PPAR-mediated reporter activation was identified in the region spanning between nt -192 to nt -173 on bovine hepcidin promoter. In contrast, the putative PPRE was detected in ruminant hepcidin promoter but not in the compatible regions of hepcidin promoter from humans, mice, rats, pigs, dogs, and cats. Consistent with the results, co-expression of PPAR and RXR did not increase the expression of hepcidin reporter prepared from these animal species. The present study reveals a novel ruminant-specific stimulation of hepcidin transcription, which suggests the regulation of hepcidin-involved iron metabolism related to hepatic lipid metabolism.