Abstract
The hepatic hormone hepcidin is the master regulator of systemic iron homeostasis. Its expression level is adjusted to alterations in iron levels, inflammatory cues, and iron requirements for erythropoiesis. Bone morphogenetic protein 6 (BMP6) contributes to the iron-dependent control of hepcidin. In addition, TGF-β1 may stimulate hepcidin mRNA expression in murine hepatocytes and human leukocytes. However, receptors and downstream signaling proteins involved in TGF-β1-induced hepcidin expression are still unclear. Here we show that TGF-β1 treatment of mouse and human hepatocytes, as well as ectopic expression of TGF-β1 in mice, increases hepcidin mRNA levels. The hepcidin response to TGF-β1 depends on functional TGF-β1 type I receptor (ALK5) and TGF-β1 type II receptor (TβRII) and is mediated by a noncanonical mechanism that involves Smad1/5/8 phosphorylation. Interestingly, increasing availability of canonical Smad2/3 decreases TGF-β1-induced hepcidin regulation, whereas the BMP6-hepcidin signal was enhanced, indicating a signaling component stoichiometry-dependent cross-talk between the two pathways. Although ALK2/3-dependent hepcidin activation by BMP6 can be modulated by each of the three hemochromatosis-associated proteins: HJV (hemojuvelin), HFE (hemochromatosis protein), and TfR2 (transferrin receptor 2), these proteins do not control the ALK5-mediated hepcidin response to TGF-β1. TGF-β1 mRNA levels are increased in mouse models of iron overload, indicating that TGF-β1 may contribute to hepcidin synthesis under these conditions. In conclusion, these data demonstrate that a complex regulatory network involving TGF-β1 and BMP6 may control the sensing of systemic and/or hepatic iron levels.
Highlights
The abbreviations used areFerroportin; BMP, bone morphogenetic protein; HH, hereditary hemochromatosis; mouse hepatocytes (mHC), primary mouse hepatocyte; TRII, TGF-1 type II receptor; SFBC, plasma iron concentration; UIBC, unsaturated iron binding capacity; ANOVA, analysis of variance
The liver-produced small peptide hormone hepcidin has emerged as a central regulator of systemic iron homeostasis [1]
We show that application of increasing amounts of TGF-1 increased hepcidin mRNA expression, which was further enhanced by addition of Bone morphogenetic protein 6 (BMP6) (Fig. 3C)
Summary
Ferroportin; BMP, bone morphogenetic protein; HH, hereditary hemochromatosis; mHC, primary mouse hepatocyte; TRII, TGF-1 type II receptor; SFBC, plasma iron concentration; UIBC, unsaturated iron binding capacity; ANOVA, analysis of variance. TGF- expression is increased in response to liver damage and enhances hepatocyte destruction, as well as hepatic stellate cell activation, resulting in myofibroblast generation and extracellular matrix deposition [25]. In murine hepatocytes [30] and hepatic stellate cells [24], TGF-1 induces both Smad2/3 and Smad1/5/8 phosphorylation in a time-dependent manner. Previous findings suggested that TGF-1 may stimulate hepcidin mRNA expression in mouse hepatocytes [31] and human leukocytes [32], but not in human hepatic carcinoma cell lines [33]. Receptors and downstream signaling proteins involved in TGF-1-induced hepcidin expression have not been investigated. We show that TGF-1 regulates hepcidin transcription in hepatocytic cell lines, primary mouse and human hepatocytes, and mice. We show that the TGF-1 response of hepcidin is mediated by ALK5- and Smad1/5/8-mediated downstream signaling
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