title: Citrate Defines a Regulatory Link Between Energy Metabolism and the Liver Hormone Hepcidin
creator: Ladeira Courelas da Silva, Ana Rita
subject: ddc-000
subject: 000 Generalities, Science
description: Iron plays a critical role as an oxygen carrier in hemoglobin as well as a constituent of iron-sulfur clusters. Increasing evidence suggests that mechanisms maintaining iron homeostasis cross-talk to intermediary metabolism. The liver hormone hepcidin is the key regulator of systemic iron metabolism. Hepcidin transcriptional control is linked to the nutrient-sensing mTOR pathway, proliferative signals, gluconeogenic responses during starvation and hormones that modulate energy metabolism. The aim of my PhD project was to investigate links between hepcidin regulation and cellular metabolism. My work describes for the first time that citrate metabolism controls hepcidin expression.   A previously reported genome-wide RNAi screen generated a first  comprehensive atlas of hepatocytic hepcidin regulators. To study metabolic signals that control hepcidin expression, I selected putative hepcidin regulators from the screening data, noting that several are specifically involved in citrate metabolism. I show that the siRNA-mediated knockdown of the enzymes that catalyze citrateconsuming reactions ACO1 (cytosolic aconitase), ACO2 (mitochondrial aconitase) and ACLY (ATP citrate lyase), as well as the inhibition of their enzymatic activities by small molecules, increases hepcidin mRNA expression in primary murine hepatocytes (PMH). Treatment of PMH with citrate furthermore results in the increase of citrate in cells and increased hepcidin expression. I further demonstrate that citrate acts intracellularly to regulate hepcidin via the BMP/SMAD signaling pathway. Injection of citrate into the tail vein of mice supports my findings that citrate increase in the liver augments hepcidin expression as well as the activity of BMP/SMAD signaling also in vivo.  All together, my results uncover the cross-talk between iron homeostasis and  intermediary metabolism, and may help to explain why iron levels are altered in  several metabolic disorders.
date: 2017
type: Dissertation
type: info:eu-repo/semantics/doctoralThesis
type: NonPeerReviewed
format: application/pdf
identifier: https://archiv.ub.uni-heidelberg.de/volltextserverhttps://archiv.ub.uni-heidelberg.de/volltextserver/22663/1/Ana%20Rita%20da%20Silva%20_PhD%20Dissertation.pdf
identifier: DOI:10.11588/heidok.00022663
identifier: urn:nbn:de:bsz:16-heidok-226631
identifier:   Ladeira Courelas da Silva, Ana Rita  (2017) Citrate Defines a Regulatory Link Between Energy Metabolism and the Liver Hormone Hepcidin.  [Dissertation]     
relation: https://archiv.ub.uni-heidelberg.de/volltextserver/22663/
rights: info:eu-repo/semantics/openAccess
rights: http://archiv.ub.uni-heidelberg.de/volltextserver/help/license_urhg.html
language: eng