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

Yu-Ji Kim,Don-Kyu Kim,Jae-Ho Jeong,Hueng-Sik Choi,Jae-Il Park,Ki Woo Kim,Daejin Lim,Ki-Sun Kim,Dong Ju Yang

doi:10.3390/antiox9060514

Abstract

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.

Highlights

Anemia of inflammation (AI), called anemia of chronic disease, is the most common type of anemia, following iron deficiency anemia [1]
An iron homeostatic hormone, is regulated through two major signaling pathways: inflammatory cytokine IL-6-dependent activation of JAK2-signal transducer and activator of transcription 3 (STAT3) signaling and excessive iron-mediated activation of bone morphogenetic protein-6 (BMP-6)-SMADs signaling [30]
We identified Small heterodimer partner-interacting leucine zipper protein (SMILE) as a transcriptional corepressor of STAT3 suppressing hepcidin production and eventual hypoferremia

Summary

Introduction

Anemia of inflammation (AI), called anemia of chronic disease, is the most common type of anemia, following iron deficiency anemia [1]. The major etiologies of AI are acute and chronic infections, autoimmune disorders, chronic kidney disease, malignancies and inflammation. Iron is absorbed into the enterocytes, circulates through blood in a form of Antioxidants 2020, 9, 514; doi:10.3390/antiox9060514 www.mdpi.com/journal/antioxidants. Antioxidants 2020, 9, 514 transferrin-bound iron and transports into another organs and tissues for utilization. Iron recycling from macrophages for erythropoiesis is required to maintain iron homeostasis [3,4]. A hepatic peptide hormone, plays a key role in iron metabolism by binding to the cell surface the iron transporter ferroportin (FPN) and triggering its internalization and degradation [5,6]

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Results

Conclusion