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Ferrata Storti Foundation
Haematologica 2019 Volume 104(9):1768-1781
Iron Metabolism & its Disorders
New thiazolidinones reduce iron overload in mouse models of hereditary hemochromatosis and β-thalassemia
Jing Liu,1, 2,# Wei Liu,1,2,# Yin Liu,1,3 Yang Miao,1 Yifan Guo,1 Haoyang Song,1 Fudi Wang,4 Hongyu Zhou,5 Tomas Ganz,6 Bing Yan3,5 and Sijin Liu1, 2
1State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China; 2University of Chinese Academy of Sciences, Beijing, China; 3School of Environmental Science and
4
Engineering, Shandong University, Shandong, China; Department of Nutrition, Nutrition
Discovery Innovation Center, Institute of Nutrition and Food Safety, School of Public Health, School of Medicine, Zhejiang University, Zhejiang, China; 5Key Laboratory for Water Quality and Conservation of the Pearl River Delta, Ministry of Education, Institute of Environmental Research at Greater Bay, Guangzhou University, Guangzhou, China and 6Department of Medicine and Department of Pathology, David Geffen School of Medicine at University of California, California, Los Angeles, CA, USA
ABSTRACT
Genetic iron-overload disorders, mainly hereditary hemochromatosis and untransfused β-thalassemia, affect a large population world- wide. The primary etiology of iron overload in these diseases is insufficient production of hepcidin by the liver, leading to excessive intes- tinal iron absorption and iron efflux from macrophages. Hepcidin agonists would therefore be expected to ameliorate iron overload in hereditary hemochromatosis and β-thalassemia. In the current study, we screened our synthetic library of 210 thiazolidinone compounds and identified three thi- azolidinone compounds, 93, 156 and 165, which stimulated hepatic hep- cidin production. In a hemochromatosis mouse model with hemochro- matosis deficiency, the three compounds prevented the development of iron overload and elicited iron redistribution from the liver to the spleen. Moreover, these compounds also greatly ameliorated iron overload and mitigated ineffective erythropoiesis in β-thalassemic mice. Compounds 93, 156 and 165 acted by promoting SMAD1/5/8 signaling through differential- ly repressing ERK1/2 phosphorylation and decreasing transmembrane pro- tease serine 6 activity. Additionally, compounds 93, 156 and 165 targeted erythroid regulators to strengthen hepcidin expression. Therefore, our hep- cidin agonists induced hepcidin expression synergistically through a direct action on hepatocytes via SMAD1/5/8 signaling and an indirect action via eythroid cells. By increasing hepcidin production, thiazolidinone com- pounds may provide a useful alternative for the treatment of iron-overload disorders.
Introduction
Hepcidin, produced by hepatocytes, is a 25-amino acid peptide hormone that plays a central role in systemic iron homeostasis. Hepcidin binds to its receptor, fer- roportin, to induce ferroportin degradation, thereby decreasing iron efflux from macrophages and hepatocytes as well as intestinal iron absorption. Hepcidin con- centration changes within a physiological range to orchestrate iron absorption, recycling and tissue distribution. However, pathological dysregulation of hepcidin causes diverse iron disorders. In particular, hepcidin deficiency results in iron-load- ing syndromes such as hereditary hemochromatosis (HH),1 β-thalassemia interme- dia2 and other iron-loading anemias.3,4 Thus, enhancing hepcidin production with suitable agonists represents a promising strategy to prevent iron accumulation in HH, β-thalassemia and other iron-loading conditions.5,6
Type 1 HH, caused by mutations of the hemochromatosis (HFE) gene, is the most common form of HH in populations of northern European origin.7 β-thalassemia,
#JL and WL contributed equally to this work
Correspondence:
BING YAN
drbingyan@yahoo.com
SIJIN LIU
sjliu@rcees.ac.cn
Received: October 21, 2018. Accepted: February 15, 2019. Pre-published: February 21, 2019.
doi:10.3324/haematol.2018.209874
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