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Epigallocatechin-3-Gallate (EGCG)-Inducible SMILE Inhibits STAT3-Mediated Hepcidin Gene Expression

 Yu-Ji Kim  ;  Ki-Sun Kim  ;  Daejin Lim  ;  Dong Ju Yang  ;  Jae-Il Park  ;  Ki Woo Kim  ;  Jae-Ho Jeong  ;  Hueng-Sik Choi  ;  Don-Kyu Kim 
 ANTIOXIDANTS, Vol.9(6) : 514, 2020-06 
Journal Title
Issue Date
FoxO1 ; IL-6 ; SMILE ; STAT3 ; anemia of chronic disease ; epigallocatechin-3-gallate ; hepcidin ; iron metabolism
Hepatic peptide hormone hepcidin, a key regulator of iron metabolism, is induced by inflammatory cytokine interleukin-6 (IL-6) in the pathogenesis of anemia of inflammation or microbial infections. Small heterodimer partner-interacting leucine zipper protein (SMILE)/CREBZF is a transcriptional corepressor of nuclear receptors that control hepatic glucose and lipid metabolism. Here, we examined the role of SMILE in regulating iron metabolism by inflammatory signals. Overexpression of SMILE significantly decreased activation of the Janus kinase 2-signal transducer and activator of transcription 3 (STAT3)-mediated hepcidin production and secretion that is triggered by the IL-6 signal in human and mouse hepatocytes. Moreover, SMILE co-localized and physically interacted with STAT3 in the nucleus in the presence of IL-6, which significantly suppressed binding of STAT3 to the hepcidin gene promoter. Interestingly, epigallocatechin-3-gallate (EGCG), a major component of green tea, induced SMILE expression through forkhead box protein O1 (FoxO1), as demonstrated in FoxO1 knockout primary hepatocytes. In addition, EGCG inhibited IL-6-induced hepcidin expression, which was reversed by SMILE knockdown. Finally, EGCG significantly suppressed lipopolysaccharide-induced hepcidin secretion and hypoferremia through induction of SMILE expression in mice. These results reveal a previously unrecognized role of EGCG-inducible SMILE in the IL-6-dependent transcriptional regulation of iron metabolism.
Appears in Collections:
2. College of Dentistry (치과대학) > Dept. of Oral Biology (구강생물학교실) > 1. Journal Papers
Yonsei Authors
Kim, Ki Woo(김기우) ORCID logo https://orcid.org/0000-0002-7790-1515
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