Physiological stress-induced corticosterone increases heme uptake via KLF4-HCP1 signaling pathway in hippocampus neurons

Iron overload has attracted much attention because of its adverse effect in increasing the risk of developing several neurodegenerative disorders. Under various pathologic conditions, a lot of heme are released. The aggregation of heme is more neurotoxic than that of iron released from the heme breakdown. Our previous studies demonstrated that psychological stress (PS) is a risk factor of cerebral iron metabolism disorders, thus causing iron accumulation in rat brains. In the present study, we found PS could increase heme uptake via heme carrier protein 1 (HCP1) in rat brains. We demonstrated that Glucocorticoid (GC), which is largely secreted under stress, could up-regulate HCP1 expression, thus promoting heme uptake in neurons. We also ascertained that HCP1 expression can be induced by GC through a transcription factor, Krüppel-like factor 4 (KLF4). These results may gain new insights into the etiology of heme uptake and iron accumulation in PS rats, and find new therapeutic targets of iron accumulation in Parkinson’s disease or Alzheimer’s disease.