| First Author | Lee JM | Year | 2018 |
| Journal | J Biol Chem | Volume | 293 |
| Issue | 34 | Pages | 13125-13133 |
| PubMed ID | 29950523 | Mgi Jnum | J:270138 |
| Mgi Id | MGI:6220541 | Doi | 10.1074/jbc.RA118.002196 |
| Citation | Lee JM, et al. (2018) The SMILE transcriptional corepressor inhibits cAMP response element-binding protein (CREB)-mediated transactivation of gluconeogenic genes. J Biol Chem 293(34):13125-13133 |
| abstractText | 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 gamma coactivator 1-alpha (PGC-1alpha) are essential for this transcriptional induction of gluconeogenic genes. PGC-1alpha 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-1alpha expression and abrogates its stimulatory effect on hepatic gluconeogenesis. However, the molecular mechanism whereby SMILE suppresses PGC-1alpha 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-1alpha expression by interacting with and disrupting the CREB/CRTC2 complex. Consequently, SMILE decreased PGC-1alpha-induced hepatic gluconeogenic gene expression. Furthermore, SMILE inhibited CREB/CRTC2-induced 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-1alpha 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-1alpha expression, an insight that may help inform potential therapeutic approaches targeting PGC-1alpha-mediated regulation of hepatic glucose metabolism. |
