Modulation of the HIF2α-NCOA4 axis in enterocytes attenuates iron loading in a mouse model of hemochromatosis

• Published in: Blood 2022-04, Vol.139 (16), p.2547-2552
• Main Authors: Das, Nupur K., Jain, Chesta, Sankar, Amanda, Schwartz, Andrew J., Santana-Codina, Naiara, Solanki, Sumeet, Zhang, Zhiguo, Ma, Xiaoya, Parimi, Sanjana, Rui, Liangyou, Mancias, Joseph D., Shah, Yatrik M.
• Format: Article
• Language: English
• Subjects: Anemia; Animals; Basic Helix-Loop-Helix Transcription Factors - metabolism; Enterocytes - metabolism; Hemochromatosis - genetics; Iron - metabolism; Iron Overload; Mice; Nuclear Receptor Coactivators - genetics; Red Cells, Iron, and Erythropoiesis; Transcription Factors - metabolism
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.2021013452

Intestinal iron absorption is activated during increased systemic demand for iron. The best-studied example is iron deficiency anemia, which increases intestinal iron absorption. Interestingly, the intestinal response to anemia is very similar to that of iron overload disorders, as both the conditions activate a transcriptional program that leads to a hyperabsorption of iron via the transcription factor hypoxia-inducible factor 2α (HIF2α). However, pathways for selective targeting of intestine-mediated iron overload remain unknown. Nuclear receptor coactivator 4 (NCOA4) is a critical cargo receptor for autophagic breakdown of ferritin and the subsequent release of iron, in a process termed ferritinophagy. Our work demonstrates that NCOA4-mediated intestinal ferritinophagy is integrated into systemic iron demand via HIF2α. To demonstrate the importance of the intestinal HIF2α/ferritinophagy axis in systemic iron homeostasis, whole-body and intestine-specific NCOA4−/− mouse lines were generated and assessed. The analyses revealed that the intestinal and systemic response to iron deficiency was not altered after disruption of intestinal NCOA4. However, in a mouse model of hemochromatosis, ablation of intestinal NCOA4 was protective against iron overload. Therefore, NCOA4 can be selectively targeted for the management of iron overload disorders without disrupting the physiological processes involved in the response to systemic iron deficiency. •Mouse models show that iron homeostasis in hemochromatosis, but not in anemia, is integrated into ferritinophagy.•Disrupting intestinal ferritinophagy protects mice from iron overload, but does not alter iron deficiency. [Display omitted]