Molecular Mechanisms Of PGC-1α Regulating Hepcidin Expression And Iron Dynamic Equilibrium

In the adult human, systemic iron levels were limited within a very narrow window. If the systemic iron balance was broken, either iron deficiency or overload will lead to a series of diseases. In the complicated signal network of systemic iron homeostasis, the small hepatic peptide hormone hepcidin has been shown to play a pivotal role. Hepcidin binds to the cell surface iron transporter ferroportinl (FPN1), inducing its internalization and degradation in lysosome, and therefore disturbs systemic iron homeostasis. Hepcidin expression is highly adaptive and robustly responses to many environmental stimuli including hypoxia, ER stress and inflammation. In particular, Hepcidin levels have been found to be elevated in patients with chronic inflammation when compared to healthy controls, and then resulted in anemia of inflammation (AI). Although it has been shown that the signal transducer and activator of transcription-3 (STAT-3) signaling mediates the upregulation of hepcidin during inflammation, the media molecule through which inflammation affects hepcidin expression and iron homeostasis is still not fully understood.Peroxisome proliferator-activated receptor-γcoactivator-1α(PGC-1α) is a transcriptional coactivator controlling multiple metabolic aspects. PGC-1αcan selectively bound with transcriptional facters (including HNF4a (hepatocyte nuclear factor 4α)). It is reported that there are conservative binding sites for HNF-4αin the human Hepcidin promoter, and amounts of Hepcidin transcripts increased in liver-specific HNF4a-null mice. On the whole of the above results of previous studies, it is easy to be found that, there seems to be inextricable link among inflammatory stimuli、PGC-1α、HNF4αand Hepcidin, but what is the specific signal transduction mechanism?To answer this question, we did research in vitro and in vivo. For the in vitro assay, adenovirus-mediated PGC-1αoverexpression in HepG2 and HuH7 human hepatoma cells, we found that PGC-1αinhibited hepcidin mRNA and protein expression in a dose-dependent manner, additionally, PGC-la antagonized LPS or IL-6 induced hepcidin expression both at the transcriptional and translational levels. Luciferase reporter assays showed that PGC-1αand HNF4αsynergistically inhibited activity on hepcidin promoter(-775～+100). Chromatin immunoprecipitation (ChIP) assays indicated that, PGC-la bound on DR-2 region in hepcidin promoter and reduced its histone 3 acetylase, and then blocked the increase of hepcidin promoter activity when challenged by LPS or IL-6. For the in vivo assay, mice were challenged with LPS to mimic acute inflammation, simultaneously intervened with tail-vein injection of PGC-la encoding adenovirus which leaded to the liver-specific overexpression of PGC-la. We measured related genes expression and the plasma parameters. the result revealed that LPS significantly suppressed PGC-la and HNF4a mRNA expression, and induced hepcidin accumulation in the liver, mice appeared serum iron deficient. Further more, PGC-la repressed hepcidin expression and LPS-induced anemia was improved by PGC-la in mice.Conclusions:PGC-1αis a critical component of the hepcidin regulation and iron metabolism in mammals, It can cooperate with HNF4a to inhibit the expression of Hepcidin. Downregulation of PGC-la and HNF4a during inflammation results in the disinhibition of Hepcidin, the expression and activity of hepcidin was increased, and eventually lead to inflammatory anemia. iron deficiency. Therefore, our results enriched the existing mechanisms for the understanding of inflammatory anemia and provided a new target molecule for the future treatment of iron disorder diseases.