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Crosstalk Between Iron Homeostasis and Metabolism

PhD Trainee
Sponsor: Scientific Committee on Iron and Heme
Program: Scientific Program
Hematology Disease Topics & Pathways:
Diseases, Biological Processes, Metabolic Disorders
Monday, December 9, 2024: 4:30 PM-5:45 PM
Room 29 (San Diego Convention Center)

Description:
Maintaining iron balance is fundamental to preserve metabolic functions and energy requirements. This session reflects the current understanding of the reciprocal relationship existing between iron homeostasis and energetic metabolism. It aims to highlight the regulatory role of heme and iron on glucose and lipid metabolism as well as the impact of metabolism on the modulation of the iron status. Novel findings will be presented about the physiologic and pathologic implications of iron-mediated regulation of metabolism, and metabolite-driven control of iron and heme homeostasis. The session will focus on b-thalassemia, sickle cell disease and obesity, and will have broad relevance to all hematologic and non-hematological diseases.

Dr. Antonella Nai will discuss the role of Transferrin Receptor2 (TFR2) in the reciprocal regulation between iron homeostasis, erythropoiesis, and glucose metabolism. TFR2 is an iron sensor acting as a brake of erythropoietin signaling in erythroid cells. Its genetic inactivation in the hematopoietic compartment enhances erythropoiesis and improves anemia in β-thalassemia. She will present unpublished data demonstrating that Tfr2 deficiency increases the metabolic activity of erythroid cells, thus promoting glucose consumption and reducing blood glycemia. This is particularly relevant in β-thalassemia, whereby glucose intolerance and diabetes are common and invalidating complications.

Dr. Wei Ying will focus on the connection between iron homeostasis and lipid metabolism. He will present findings related to the role of iron homeostasis in regulating hepatocyte lipogenesis and neighboring cell responses, including hepatic stellate cells, and describe how alterations of these mechanisms drive non-alcoholic fatty liver disease, steatohepatitis and obesity.

Dr. Leitinger will share how heme triggers a unique bioenergetic switch in macrophages, characterized by a metabolic shift from oxidative phosphorylation towards glucose consumption, and its critical role in the effective clearance and detoxification of heme in sickle cell disease. Based on the previous identification of the phosphofructokinase PFKFB3 as key mediator of the metabolic switching in heme-detoxifying macrophages, he will present data about a potential therapeutic strategy involving the inhibition of PFKFB3 in a mouse model of sickle cell disease. Furthermore, the general clinical relevance of these processes for patients with hemolytic disorders will be discussed.

Chair:
Francesca Vinchi, PhD, New York Blood Center
Disclosures:
Vinchi: PharmaNutra: Research Funding; CSL Vifor: Research Funding; Silence Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacosmos: Consultancy; RallyBio: Consultancy.

Maintaining iron balance is fundamental to preserve metabolic functions and energy requirements. This session reflects the current understanding of the reciprocal relationship existing between iron homeostasis and energetic metabolism. It aims to highlight the regulatory role of heme and iron on glucose and lipid metabolism as well as the impact of metabolism on the modulation of the iron status. Novel findings will be presented about the physiologic and pathologic implications of iron-mediated regulation of metabolism, and metabolite-driven control of iron and heme homeostasis. The session will focus on b-thalassemia, sickle cell disease and obesity, and will have broad relevance to all hematologic and non-hematological diseases.

Dr. Antonella Nai will discuss the role of Transferrin Receptor2 (TFR2) in the reciprocal regulation between iron homeostasis, erythropoiesis, and glucose metabolism. TFR2 is an iron sensor acting as a brake of erythropoietin signaling in erythroid cells. Its genetic inactivation in the hematopoietic compartment enhances erythropoiesis and improves anemia in β-thalassemia. She will present unpublished data demonstrating that Tfr2 deficiency increases the metabolic activity of erythroid cells, thus promoting glucose consumption and reducing blood glycemia. This is particularly relevant in β-thalassemia, whereby glucose intolerance and diabetes are common and invalidating complications.

Dr. Wei Ying will focus on the connection between iron homeostasis and lipid metabolism. He will present findings related to the role of iron homeostasis in regulating hepatocyte lipogenesis and neighboring cell responses, including hepatic stellate cells, and describe how alterations of these mechanisms drive non-alcoholic fatty liver disease, steatohepatitis and obesity.

Dr. Leitinger will share how heme triggers a unique bioenergetic switch in macrophages, characterized by a metabolic shift from oxidative phosphorylation towards glucose consumption, and its critical role in the effective clearance and detoxification of heme in sickle cell disease. Based on the previous identification of the phosphofructokinase PFKFB3 as key mediator of the metabolic switching in heme-detoxifying macrophages, he will present data about a potential therapeutic strategy involving the inhibition of PFKFB3 in a mouse model of sickle cell disease. Furthermore, the general clinical relevance of these processes for patients with hemolytic disorders will be discussed.

Antonella Nai, PhD

IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milano, Italy

Wei Ying, PhD

Medicine, University of California San Diego, La Jolla, CA; University of California San Diego, La Jolla, CA

Norbert Leitinger

University of Virginia, Charlottesville, VA

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