BACKGROUND & AIMS: Iron deficiency and iron overload affect over a billion people worldwide. Dietary iron absorption in the small intestine is required for systemic iron homeostasis. Ferroportin (FPN) is the only characterized, mammalian, basolateral iron exporter. Despite the importance of FPN in maintaining iron homeostasis, its in vivo mechanisms of regulation are unclear. METHODS: Systemic iron homeostasis was assessed in mice with intestine-specific disruption of genes encoding the von Hippel-Lindau tumor suppressor protein (Vhl), hypoxia-inducible factor (HIF)-1α, HIF-2α, and aryl hydrocarbon nuclear translocator (ARNT). RESULTS: We observed biphasic regulation of Fpn during iron deficiency. Fpn was rapidly induced under conditions of low iron, which required the transcription factor HIF-2α. Targeted disruption of HIF-2α in the intestine inhibited Fpn induction in mice with low iron, through loss of transcriptional activation. Analysis of the Fpn promoter and in vivo chromatin immunoprecipitation assays demonstrated that HIF-2α directly binds to the Fpn promoter and induces its expression, indicating a mechanism of transcriptional regulation of Fpn following changes in systemic levels of iron. During chronic iron deficiency, FPN protein levels also increased, via increased stability through a HIF-2α-independent pathway. CONCLUSIONS: In mice, expression of the gene that encodes Fpn and its protein levels are regulated by distinct pathways to provide a rapid and sustained response to acute and chronic iron deficiency. Therapies that target FPN might be developed for patients with iron-related disorders.
BACKGROUND & AIMS:Iron deficiency and iron overload affect over a billion people worldwide. Dietary iron absorption in the small intestine is required for systemic iron homeostasis. Ferroportin (FPN) is the only characterized, mammalian, basolateral iron exporter. Despite the importance of FPN in maintaining iron homeostasis, its in vivo mechanisms of regulation are unclear. METHODS: Systemic iron homeostasis was assessed in mice with intestine-specific disruption of genes encoding the von Hippel-Lindau tumor suppressor protein (Vhl), hypoxia-inducible factor (HIF)-1α, HIF-2α, and aryl hydrocarbon nuclear translocator (ARNT). RESULTS: We observed biphasic regulation of Fpn during iron deficiency. Fpn was rapidly induced under conditions of low iron, which required the transcription factor HIF-2α. Targeted disruption of HIF-2α in the intestine inhibited Fpn induction in mice with low iron, through loss of transcriptional activation. Analysis of the Fpn promoter and in vivo chromatin immunoprecipitation assays demonstrated that HIF-2α directly binds to the Fpn promoter and induces its expression, indicating a mechanism of transcriptional regulation of Fpn following changes in systemic levels of iron. During chronic iron deficiency, FPN protein levels also increased, via increased stability through a HIF-2α-independent pathway. CONCLUSIONS: In mice, expression of the gene that encodes Fpn and its protein levels are regulated by distinct pathways to provide a rapid and sustained response to acute and chronic iron deficiency. Therapies that target FPN might be developed for patients with iron-related disorders.
Authors: Nupur K Das; Andrew J Schwartz; Gabrielle Barthel; Naohiro Inohara; Qing Liu; Amanda Sankar; David R Hill; Xiaoya Ma; Olivia Lamberg; Matthew K Schnizlein; Juan L Arqués; Jason R Spence; Gabriel Nunez; Andrew D Patterson; Duxin Sun; Vincent B Young; Yatrik M Shah Journal: Cell Metab Date: 2019-11-07 Impact factor: 27.287
Authors: Erik R Anderson; Matthew Taylor; Xiang Xue; Sadeesh K Ramakrishnan; Angelical Martin; Liwei Xie; Bryce X Bredell; Sara Gardenghi; Stefano Rivella; Yatrik M Shah Journal: Proc Natl Acad Sci U S A Date: 2013-11-26 Impact factor: 11.205
Authors: Andrew J Schwartz; Nupur K Das; Sadeesh K Ramakrishnan; Chesta Jain; Mladen T Jurkovic; Jun Wu; Elizabeta Nemeth; Samira Lakhal-Littleton; Justin A Colacino; Yatrik M Shah Journal: J Clin Invest Date: 2018-12-10 Impact factor: 14.808