AMPK-dependent repression of hepatic gluconeogenesis via disruption of CREB·CRTC2 complex by orphan nuclear receptor small heterodimer partner

Ji Min Lee, Woo Young Seo, Kwang Hoon Song, Dipanjan Chanda, Yong Deuk Kim, Don Kyu Kim, Min Woo Lee, Dongryeol Ryu, Yong Hoon Kim, Jung Ran Noh, Chul Ho Lee, John Y.L. Chiang, Seung Hoi Koo, Hueng Sik Choi

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99 Citations (Scopus)

Abstract

Orphan nuclear receptor small heterodimer partner (SHP) plays a key role in transcriptional repression of gluconeogenic enzyme gene expression. Here, we show that SHP inhibited protein kinase A-mediated transcriptional activity of cAMP-response element-binding protein (CREB), a major regulator of glucose metabolism, to modulate hepatic gluconeogenic gene expression. Deletion analysis of phosphoenolpyruvate carboxykinase (PEPCK) promoter demonstrated that SHP inhibited forskolin-mediated induction of PEPCK gene transcription via inhibition of CREB transcriptional activity. In vivo imaging demonstrated that SHP inhibited CREB-regulated transcription coactivator 2 (CRTC2)-mediated cAMP-response element-driven promoter activity. Furthermore, overexpression of SHP using adenovirus SHP decreased CRTC2-dependent elevations in blood glucose levels and PEPCK or glucose-6-phosphatase (G6Pase) expression in mice. SHP and CREB physically interacted and were co-localized in vivo. Importantly, SHP inhibited both wild type CRTC2 and S171A (constitutively active form of CRTC2) coactivator activity and disrupted CRTC2 recruitment on the PEPCK gene promoter. In addition, metformin or overexpression of a constitutively active form of AMPK (Ad-CA-AMPK) inhibited S171A-mediated PEPCK and G6Pase gene expression, and hepatic glucose production and knockdown of SHP partially relieved the metformin- and Ad-CA-AMPK-mediated repression of hepatic gluconeogenic enzyme gene expression in primary rat hepatocytes. In conclusion, our results suggest that a delayed effect of metformin-mediated induction of SHP gene expression inhibits CREB-dependent hepatic gluconeogenesis.

Original languageEnglish
Pages (from-to)32182-32191
Number of pages10
JournalJournal of Biological Chemistry
Volume285
Issue number42
DOIs
Publication statusPublished - 2010 Oct 15
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Lee, J. M., Seo, W. Y., Song, K. H., Chanda, D., Kim, Y. D., Kim, D. K., Lee, M. W., Ryu, D., Kim, Y. H., Noh, J. R., Lee, C. H., Chiang, J. Y. L., Koo, S. H., & Choi, H. S. (2010). AMPK-dependent repression of hepatic gluconeogenesis via disruption of CREB·CRTC2 complex by orphan nuclear receptor small heterodimer partner. Journal of Biological Chemistry, 285(42), 32182-32191. https://doi.org/10.1074/jbc.M110.134890