NCOA4 Mediates Mobilization of Hepatic Iron Stores after Blood Loss

The intracellular protein NCOA4 mediates the autophagic degradation of ferritin in vitro (Mancias et al., Nature 2014; Dowdle et al., Nat Cell Biol 2014); mice with global Ncoa4 disruption show hyperferremia, microcytic anemia, and ferritin accumulation in multiple organs, including liver (Bellelli et al., Cell Rep 2016). Here, we dissect the requirement for NCOA4 in hepatic iron mobilization after acute blood loss, using Ncoa4-targeting siRNA that was conjugated to triantennary N-acetylgalactosamine (GalNAc-Ncoa4 siRNA) to promote uptake by hepatocytes. On experimental day 0, 8-week-old female C57BL/6N mice underwent a single 500 μl phlebotomy, which was followed immediately by intraperitoneal volume replacement (saline) and concomitant subcutaneous injection of either GalNAc-Ncoa4 siRNA (3 mg/kg) or saline vehicle. The phlebotomized mice then underwent a second, terminal blood collection and organ harvest at either 3 days later (when mice subjected to this phlebotomy protocol are known to reach their hematocrit nadir) or 7 days later (when mice subjected to this phlebotomy protocol are known to exhibit substantial hematocrit recovery). To provide an experimental baseline, a group of 8-week-old mice that were not phlebotomized and did not receive a subcutaneous injection of either saline or GalNAc-Ncoa4-siRNA were analyzed on experimental day 0.Injection of GalNAc-Ncoa4 siRNA immediately after phlebotomy resulted in marked hepatic Ncoa4 knockdown at both 3 and 7 days afte...
Source: Blood - Category: Hematology Authors: Tags: 102. Regulation of Iron Metabolism: Poster I Source Type: research