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.
Bibliographical noteFunding 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.
© 2018 Lee et al.
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology