The SMILE transcriptional corepressor inhibits cAMP response element– binding protein (CREB)–mediated transactivation of gluconeogenic genes

Ji Min Lee, Hye Sook Han, Yoon Seok Jung, Robert A. Harris, Seung-Hoi Koo, Hueng Sik Choi

Research output: Contribution to journalArticle

Abstract

Under fasting conditions, activation of several hepatic genes sets the stage for gluconeogenesis in the liver. cAMP response element– binding protein (CREB), CREB-regulated transcription coactivator 2 (CRTC2), and peroxisome proliferator–activated receptor coactivator 1-alpha (PGC-1) are essential for this transcriptional induction of gluconeogenic genes. PGC-1 induction is mediated by activation of a CREB/CRTC2 signaling complex, and recent findings have revealed that small heterodimer partner–interacting leucine zipper protein (SMILE), a member of the CREB/ATF family of basic region–leucine zipper (bZIP) transcription factors, is an insulin-inducible corepressor that decreases PGC-1 expression and abrogates its stimulatory effect on hepatic gluconeogenesis. However, the molecular mechanism whereby SMILE suppresses PGC-1 expression is unknown. Here, we investigated SMILE’s effects on the CREB/CRTC2 signaling pathway and glucose metabolism. We found that SMILE significantly inhibits CREB/ CRTC2-induced PGC-1 expression by interacting with and disrupting the CREB/CRTC2 complex. Consequently, SMILE decreased PGC-1–induced hepatic gluconeogenic gene expression. Furthermore, SMILE inhibited CREB/CRTC2-in-duced phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) gene expression by directly repressing the expression of these genes and by indirectly inhibiting the expression of PGC-1 via CREB/CRTC2 repression. Indeed, enhanced gluconeogenesis and circulating blood glucose levels in mice injected with an adenovirus construct containing a constitutively active CRTC2 variant (CRTC2–S171A) were significantly reduced by WT SMILE, but not by leucine zipper–mutated SMILE. These results reveal that SMILE represses CREB/CRTC2-induced PGC-1 expression, an insight that may help inform potential therapeutic approaches targeting PGC-1–mediated regulation of hepatic glucose metabolism.

Original languageEnglish
Pages (from-to)13125-13133
Number of pages9
JournalJournal of Biological Chemistry
Volume293
Issue number34
DOIs
Publication statusPublished - 2018 Jan 1

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Cyclic AMP Response Element-Binding Protein
Co-Repressor Proteins
Transcription
Transcriptional Activation
Genes
Gluconeogenesis
Liver
Gene Expression
Metabolism
Gene expression
Chemical activation
Glucose
Leucine Zippers
Glucose-6-Phosphatase
Phosphoenolpyruvate
Peroxisomes
Fasteners
Adenoviridae
Leucine
Blood Glucose

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

The SMILE transcriptional corepressor inhibits cAMP response element– binding protein (CREB)–mediated transactivation of gluconeogenic genes. / Lee, Ji Min; Han, Hye Sook; Jung, Yoon Seok; Harris, Robert A.; Koo, Seung-Hoi; Choi, Hueng Sik.

In: Journal of Biological Chemistry, Vol. 293, No. 34, 01.01.2018, p. 13125-13133.

Research output: Contribution to journalArticle

Lee, Ji Min ; Han, Hye Sook ; Jung, Yoon Seok ; Harris, Robert A. ; Koo, Seung-Hoi ; Choi, Hueng Sik. / The SMILE transcriptional corepressor inhibits cAMP response element– binding protein (CREB)–mediated transactivation of gluconeogenic genes. In: Journal of Biological Chemistry. 2018 ; Vol. 293, No. 34. pp. 13125-13133.
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