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 journalArticlepeer-review

22 Citations (Scopus)

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 Aug 24

Bibliographical note

Funding Information:
This work was supported through the National Research Foundation of Korea (NRF) by National Creative Research Initiatives Grant 20110018305 (to H.-S. C) and National Research Foundation of Korea Grants 2015R1A2A1A01006687, 2017M3A9D5A01052447, and 2015R1A5A1009024 to (S.-H. K). The work was also supported by a grant from Korea University, Seoul, Korea (to S.-H. K.). The authors declare that they have no conflicts of interest with the contents of this article.

Publisher Copyright:
© 2018 Lee et al.

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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