PUBLICATION
Small molecule inhibitors of NFkB reverse iron overload and hepcidin deregulation in a zebrafish model for Hereditary Hemochromatosis Type 3
- Authors
- Basu, S., Jalodia, K., Ranjan, S., Yeh, J.J., Peterson, R.T., Sachidanandan, C.
- ID
- ZDB-PUB-180614-17
- Date
- 2018
- Source
- ACS Chemical Biology 13(8): 2143-2152 (Journal)
- Registered Authors
- Peterson, Randall, Sachidanandan, Chetana, Yeh, Jing-Ruey (Joanna)
- Keywords
- none
- MeSH Terms
-
- Animals
- Disease Models, Animal
- Gene Knockdown Techniques
- Hemochromatosis/drug therapy*
- Hemochromatosis/metabolism
- Hepcidins/genetics
- Hepcidins/metabolism
- Iron/metabolism
- NF-kappa B/antagonists & inhibitors*
- NF-kappa B/genetics
- NF-kappa B/metabolism
- Receptors, Transferrin/deficiency*
- Receptors, Transferrin/genetics
- Receptors, Transferrin/metabolism
- Signal Transduction/drug effects
- Thiophenes/pharmacology
- Thiophenes/therapeutic use*
- Up-Regulation/drug effects
- Zebrafish/embryology
- Zebrafish/genetics
- Zebrafish/physiology
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- PubMed
- 29897731 Full text @ ACS Chem. Biol.
Citation
Basu, S., Jalodia, K., Ranjan, S., Yeh, J.J., Peterson, R.T., Sachidanandan, C. (2018) Small molecule inhibitors of NFkB reverse iron overload and hepcidin deregulation in a zebrafish model for Hereditary Hemochromatosis Type 3. ACS Chemical Biology. 13(8):2143-2152.
Abstract
Hereditary hemochromatosis (HH) is one of the most common genetic disorders in Caucasian populations, with no viable therapeutic options except phlebotomy. We describe a zebrafish model of human HH (HH) created by targeted mutagenesis of the gene encoding Transferrin receptor 2 (tfr2). TFR2 mutations in humans lead to HH Type 3, a rare but severe form of the disease. The tfr2 mutant model in zebrafish recapitulates the defining features of HH3; iron overload and suppression of hepcidin, the iron regulatory hormone. Using in vivo chemical screens in zebrafish embryos, we identify a new small molecule inducer of hepcidin: SC-514, a specific chemical inhibitor of NFkB signaling. Using independent small molecule inhibitors of NFkB pathway we demonstrate that inhibition of NFkB signaling causes induction of hepcidin transcript and reduction of iron overload in the HH3 model. This first successful chemical intervention for Hereditary Hemochromatosis may also have relevance in treatment of other very prevalent iron regulatory iron overload disorders such as Thalassemia.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping