Abstract
Liver cells communicate with the extracellular environment to take up nutrients via endocytosis. Iron uptake is essential for metabolic activities and cell homeostasis. Here, we investigated the role of the endocytic system for maintaining iron homeostasis. We specifically depleted the small GTPase Rab5 in the mouse liver, causing a transient loss of the entire endo-lysosomal system. Strikingly, endosome depletion led to a fast reduction of hepatic iron levels, which was preceded by an increased abundance of the iron exporter ferroportin. Compensatory changes in livers of Rab5-depleted mice include increased expression of transferrin receptor 1 as well as reduced expression of the iron-regulatory hormone hepcidin. Serum iron indices (serum iron, free iron binding capacity and total iron binding capacity) in Rab5-KD mice were increased, consistent with an elevated splenic and hepatic iron export. Our data emphasize the critical importance of the endosomal compartments in hepatocytes to maintain hepatic and systemic iron homeostasis in vivo. The short time period (between day four and five) upon which these changes occur underscore the fast dynamics of the liver iron pool.
Highlights
To cite this version: Christoph Metzendorf, Anja Zeigerer, Sarah Seifert, Richard Sparla, Bahar Najafi, et al
Endosome depletion led to a fast reduction of hepatic iron levels, which was preceded by an increased abundance of the iron exporter ferroportin
Our data emphasize the critical importance of the endosomal compartments in hepatocytes to maintain hepatic and systemic iron homeostasis in vivo
Summary
Endosome depletion in hepatocytes causes reduced hepatic iron levels. To investigate the role of the endo-lysosomal system for maintaining iron homeostasis, we silenced the three isoforms of Rab[5] (Rab5a, b, c)[28, 29]. Reduced hepcidin expression observed in Rab5-KD livers (Fig. 2A) will contribute to the stabilization of ferroportin protein on the cell membrane of hepatocytes[15, 16, 38] These findings are consistent with data obtained by a systems biology approach which predicted that the liver iron pool is highly dynamic and is maintained through a high iron uptake-rate in addition to iron storage in ferritin[39]. Consistent with decreased hepatic iron concentrations, we observed significantly reduced Bmp[6] and hepcidin mRNA levels as well as reduced SMAD1/5/8 phosphorylation at day five post-RNAi (Fig. 2A–C), whereby reduced Bmp[6] mRNA expression preceded the hepcidin response by one day (Fig. 2A and B) These findings suggest that the iron sensing process adequately responds to decreased hepatic iron levels in endosome-depleted livers, despite elevated levels of the hepcidin activator TFR2 (Fig. 1F). Compensatory responses to counteract hepatic iron deficiency are inactive in the absence of the endosomal system, causing a negative feedback that worsens hepatocyte iron depletion
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