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 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 (US)
Pages (from-to)13125-13133
Number of pages9
JournalJournal of Biological Chemistry
Volume293
Issue number34
DOIs
StatePublished - Jan 1 2018
Externally publishedYes

Fingerprint

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; 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 ; 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.
@article{106c65d000c14240ab5f88dceb8d5544,
title = "The SMILE transcriptional corepressor inhibits cAMP response element– binding protein (CREB)–mediated transactivation of gluconeogenic genes",
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.",
author = "Lee, {Ji Min} and Han, {Hye Sook} and Jung, {Yoon Seok} and Robert Harris and Koo, {Seung Hoi} and Choi, {Hueng Sik}",
year = "2018",
month = "1",
day = "1",
doi = "10.1074/jbc.RA118.002196",
language = "English (US)",
volume = "293",
pages = "13125--13133",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "34",

}

TY - JOUR

T1 - The SMILE transcriptional corepressor inhibits cAMP response element– binding protein (CREB)–mediated transactivation of gluconeogenic genes

AU - Lee, Ji Min

AU - Han, Hye Sook

AU - Jung, Yoon Seok

AU - Harris, Robert

AU - Koo, Seung Hoi

AU - Choi, Hueng Sik

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85052128454&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85052128454&partnerID=8YFLogxK

U2 - 10.1074/jbc.RA118.002196

DO - 10.1074/jbc.RA118.002196

M3 - Article

C2 - 29950523

AN - SCOPUS:85052128454

VL - 293

SP - 13125

EP - 13133

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 34

ER -