Involvement of estrogen-related receptors in the regulatory expression of hepcidin and their relationship to hepatitis in beef cattle.

Hepcidin (HEPC) is a liver-derived hormone that regulates systemic iron homeostasis. We previously clarified that the mechanism of regulation of human and mouse HEPC expression cannot necessarily be applied to bovine HEPC. This study explored the effects of estrogen-related receptors (ERRs) on the transcription of bovine HEPC and the regulatory expression of ERRs in the liver of beef cattle with hepatitis. ERRβ and ERRγ stimulated the expression of a reporter with the bovine HEPC promoter in a cell culture study. Co-expression of PGC-1α enhanced ERRβ- or ERRγ-induced bovine HEPC transcription in HepG2 cells. Expression levels of hepatic genes were evaluated in 49 Japanese Black beef cattle: 13 cattle had diseased liver with hepatitis. The expression levels of ERRβ and ERRγ tended to be higher in the lesional areas of the liver than in the non-lesional areas in beef cattle with hepatitis. The expression levels of genes related to ferroptosis and pericentral (PC) zone were generally higher in lesional areas of the liver. Hepatic ERRβ and ERRγ were highly related to the expression levels of ferroptosis- and PC zone-related genes, but not periportal (PP) zone-related genes. The expression of HEPC was comparable between non-lesional and lesional areas of the liver. Taken together, the in vitro data on HEPC transcription and the in vivo data on hepatic gene expression suggested that the increased expression of ERRβ and ERRγ may be involved in HEPC expression in ferroptotic hepatocytes located in the PC zone of beef cattle with hepatitis.