AMPK-dependent Repression of Hepatic Gluconeogenesis via Disruption of CREB center dot CRTC2 Complex by Orphan Nuclear Receptor Small Heterodimer Partner

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

来源：Journal of Biological Chemistry, 2010, 285(42): 32182-32191.

DOI：10.1074/jbc.M110.134890

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.

• 出版日期2010-10-15
• 单位河北医科大学