Serum iron variation is circadian-regulated and linked to the harmonic circadian oscillations of erythropoiesis and hepaticTfrcexpression in mice

Abstract

Serum iron has long been thought to exhibit diurnal variation and is subsequently considered an unreliable biomarker of systemic iron status. Circadian regulation (endogenous ~24-hour periodic oscillation of a biologic function) governs many critical physiologic processes. It is unknown whether serum iron levels are regulated by circadian machinery; likewise, the circadian nature of key players of iron homeostasis is unstudied. Here we show that serum iron and hepatic transferrin receptor (TfR) gene (Tfrc) expression exhibit circadian regulation. Daily oscillations of both serum iron and hepatic Tfrc expression are maintained in mice housed in constant darkness, where oscillation reflects an endogenous circadian period. However, oscillations of both serum iron and hepatic Tfrc were ablated when circadian machinery was disrupted in Bmal1 knockout mice. This study provides the first confirmatory evidence that serum iron is circadian regulated and uncovers liver-specific circadian regulation of TfR, a major player in cellular iron uptake.