Biomaterial Database

Hepatic hepcidin/intestinal HIF-2α axis maintains iron absorption during iron deficiency and overload. 2019

Andrew J Schwartz, and Nupur K Das, and Sadeesh K Ramakrishnan, and Chesta Jain, and Mladen T Jurkovic, and Jun Wu, and Elizabeta Nemeth, and Samira Lakhal-Littleton, and Justin A Colacino, and Yatrik M Shah

Department of Molecular and Integrative Physiology, and.

Iron-related disorders are among the most prevalent diseases worldwide. Systemic iron homeostasis requires hepcidin, a liver-derived hormone that controls iron mobilization through its molecular target ferroportin (FPN), the only known mammalian iron exporter. This pathway is perturbed in diseases that cause iron overload. Additionally, intestinal HIF-2α is essential for the local absorptive response to systemic iron deficiency and iron overload. Our data demonstrate a hetero-tissue crosstalk mechanism, whereby hepatic hepcidin regulated intestinal HIF-2α in iron deficiency, anemia, and iron overload. We show that FPN controlled cell-autonomous iron efflux to stabilize and activate HIF-2α by regulating the activity of iron-dependent intestinal prolyl hydroxylase domain enzymes. Pharmacological blockade of HIF-2α using a clinically relevant and highly specific inhibitor successfully treated iron overload in a mouse model. These findings demonstrate a molecular link between hepatic hepcidin and intestinal HIF-2α that controls physiological iron uptake and drives iron hyperabsorption during iron overload.

UI	MeSH Term	Description	Entries
D007408	Intestinal Absorption	Uptake of substances through the lining of the INTESTINES.	Absorption, Intestinal
D007501	Iron	A metallic element with atomic symbol Fe, atomic number 26, and atomic weight 55.85. It is an essential constituent of HEMOGLOBINS; CYTOCHROMES; and IRON-BINDING PROTEINS. It plays a role in cellular redox reactions and in the transport of OXYGEN.	Iron-56,Iron 56
D008099	Liver	A large lobed glandular organ in the abdomen of vertebrates that is responsible for detoxification, metabolism, synthesis and storage of various substances.	Livers
D008822	Mice, Transgenic	Laboratory mice that have been produced from a genetically manipulated EGG or EMBRYO, MAMMALIAN.	Transgenic Mice,Founder Mice, Transgenic,Mouse, Founder, Transgenic,Mouse, Transgenic,Mice, Transgenic Founder,Transgenic Founder Mice,Transgenic Mouse
D004195	Disease Models, Animal	Naturally-occurring or experimentally-induced animal diseases with pathological processes analogous to human diseases.	Animal Disease Model,Animal Disease Models,Disease Model, Animal
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000090463	Iron Deficiencies	Deficient amounts of iron in the body as a result of blood loss, diets deficient in iron, or an iron uptake or storage disorder.	Hypoferritinemia,Iron Deficiency,Latent Iron Deficiency,Sideropenia,Deficiencies, Iron,Deficiencies, Latent Iron,Deficiency, Iron,Deficiency, Latent Iron,Hypoferritinemias,Iron Deficiencies, Latent,Iron Deficiency, Latent,Latent Iron Deficiencies,Sideropenias
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D051379	Mice	The common name for the genus Mus.	Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus
D051792	Basic Helix-Loop-Helix Transcription Factors	A family of DNA-binding transcription factors that contain a basic HELIX-LOOP-HELIX MOTIF.	Basic Helix-Loop-Helix Transcription Factor,bHLH Protein,bHLH Transcription Factor,bHLH Proteins,bHLH Transcription Factors,Basic Helix Loop Helix Transcription Factor,Basic Helix Loop Helix Transcription Factors,Factor, bHLH Transcription,Protein, bHLH,Transcription Factor, bHLH,Transcription Factors, bHLH