Orphan Nuclear Receptor ERRgamma and Iron Homeostasis

Orphan Nuclear Receptor ERRgamma
and Iron Homeostasis
Hueng-Sik Choi Ph.D.
Center for Nuclear Receptor Signals
Hormone Research Institute
Chonnam National University
Signal Transduction mediated by Hormones
Growth Factors
Cytokines
Peptide Hormones
Steroids
Vitamin D
Retinoic Acid
2nd Messenger
NR NR
HRE
Structure and mode of action of nuclear receptors
Molecular and Cellular Endocrinology (2010), doi:10.1016/j.mce.2010.06.018
Orphan Nuclear Receptor Timeline
Lazar MA et. al., J Mol Endo (2013), in press
ERR (Estrogen-Related Receptor)
A. Structure
AF-1
DBD
LBD
18.7%
93.3%
57.2%
mERRα
mERRβ
58.2%
98.9%
73.1%
mERRγ
B. Expression
- ERRα: widespread, especially CNS
- ERRβ: kidney, heart
- ERRγ: pancreas, brain, liver, lung,bone marrow, adrenal glands, thyroid glands, trachea, spinal cord
C. DNA binding
- binds as monomers to the extended half-site TNAAGGTCA, which is also recognized by FTF-F1,
and as homodimers or heterodimers to the consensus estrogen responsive element
D. Target gene
- ERRα : lactoferrin, TRα, osteopontin, MCAD (medium-chain acyl CoA dehtdrogenase)
- ERRγ : PDK4, SHP, DAX-1, Plk2
ERRγ and disease
Liver disease
Obesity
Diabetes
Renal disease
Infection
Inflammation
ERRγ
Cancer Biology
Cardiovascular
disease
Bone biology
Neurobiology
The role of hepcidin in maintenance of iron homeostasis
Tomas Ganz and Elizabeta Nemeth
Biochimica et Biophysica Acta 1823 (2012) 1434–1443
Regulation of iron metabolism by Hepcidin
Nature Reviews Endocrinology 6, 26-33, 2010
Hepcidin Gene Transcription and Cell Signals
Pietrangelo A, Journal of Hepatology 2011 vol. 54 j 173–181
Hepcidin, iron partitioning, and infectious pathogens
Hal Drakesmith and Andrew M. Prentice; Science 338, 768 (2012)
Host and Pathogen Interaction in Salmonella Infection
Falkow S. et al, Nature Review Microbiology 2:747, 2004
Serum iron levels by Salmonella infection
ERRγ and Hepcidin expression by Salmonella infection
(hepcidin)
Serum iron levels in IL-6 / TNF-α KO mice
ERRγ and Hepcidin gene expression in IL-6 KO mice
(hepcidin)
Hepatic ERRγ expression by IL-6
Mice liver injected with IL-6
Regulation of ERRγ expression by IL-6
AML12 cells
ERRγ expression is regulated by IL-6 signaling
Rat primary
Hepatocytes
AML12 cells
IL-6 signaling induces ERRγ gene transcription
IL-6 signaling induces ERRγ gene transcription
Salmonella
JAK
TF
STAT3
IL-6
JAK
ERRγ
?
FPN
Macrophage
Fe-Tf
Hamp
hepcidin
Hepatocytes
ERRγ regulates serum iron levels in vivo
ERRγ regulates serum iron levels in vivo
ERRγ regulates serum iron levels in vivo
ERRγ regulates Hepcidin gene expression
Rat primary Hepatocytes
AML12 cells
ERRγ directly regulates Hepcidin gene transcription
Inverse agonist ?
Salmonella
JAK
TF
STAT3
IL-6
JAK
FPN
Macrophage
Fe-Tf
ERRγ
Hamp
hepcidin
Hepatocytes
GSK5182 is inverse agonist of orphan nuclear receptor ERRγ
Zuercher et. al., Bioorg.Med.Lett. 16(4):821, 2006
ERα
ERRγ
Affinity and Pharmacokinetics of GSK5182
Surface Plasmon Resonance
Pharmacokinetics
GSK5182 inhibits Hepcidin gene expression
(hepcidin)
In vivo imaging of hepatic Hamp-Luc and Hamp
ERREmut-Luc activity by GSK5182
Ad-Hamp ERRE
mut - Luc
Ad-Hamp wt - Luc
- Salmonella
+ Salmonella
+ Sal - GSK5182
GSK5182 restores salmonella-mediated reduction of
serum iron levels
GSK5182 inhibits salmonella-mediated Hepcidin expression
GSK5182 inhibits Salmonella-mediated Hepcidin expression
Hepatic acute-phase response gene expression
GSK5182 inhibits Hepcidin-mediated FPN degradation
GSK5182 decreases Salmonella-mediated iron
accumulation in liver and spleen by
GSK5182 inhibits salmonella growth via regulation of
Hepcidin expression
GSK5182 inhibits salmonella growth via regulation of
Hepcidin expression
GSK5182 inhibits Salmonella growth via regulation of
Hepcidin expression
Control
GSK5182
Salmonella
Salmonella
+ GSK5182
Intracellular iron levels and Salmonella count within
liver macrophage
Effect of GSK5182 on salmonella-mediated lethal shock
Hepcidin peptide reverses the effect of GSK5182 on
Salmonella-mediated hypoferremia
Hepcidin peptide reverses the effect of GSK5182 on
Salmonella growth
Hepcidin peptide reverses the antimicrobial effect
of GSK5182
ERRγ regulates iron metabolism through
induction of Hepcidin
Hypoferremia of infection: a double-edged sword?
Nat Med. 2014 Apr 8;20(4):335-337
Iron ERRs with Salmonella
Cell Host Microbe. 2014 May14;15(5):515-516
Chonnam National University
Center for Nuclear Receptor Signals
Don-Kyu Kim, Soon-Young Na, Yong-Soo Lee, Ji Min Lee,
Jaganath Misra, Yoon Suk Jeong, Yaochen Zhang
Chonnam National University
Hyon E. Choy
Jung-Joon Min
Seok-Yong Choi
Tae-Hoon Lee
Jae-Ho Jeong
Seoul National University
Dr. Seung Bum Park
Minseok Koh
Dong-A University
Dr. Hwan Tae Park
Korea Research Institute of
Bioscience and Biotechnology
Chul-Ho Lee
Yong-Hoon Kim
Gil-Tae Gang
Lee Gil Ya Cancer and Diabetes
Institute
Dr. Byung-Chul Oh
GIST
Dr. Jae Il Kim
KAIST
Dr. Won-Il Jeong

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