Diabetes 2013 July-15

 

Regulation of hepatic insulin sensitivity by activating signal co-integrator-2

Biochem J. 2012 Nov 1;447(3):437-47.

Geun Hyang KIM*1, Kyung Jin LEE*1, Gyun-Sik OH*, Jin YOON*, Hae Won KIM* and Seung-Whan KIM*2

*Department of Pharmacology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 138-736, Korea, †Bio-medical Institute of Technology, University of Ulsan College of Medicine, Seoul 138-736, Korea.

 

ASC-2 (activating signal cointegrator-2, also known as AIB3 and NCoA6) is a transcriptional co-activator and regulates insulin secretion and b-cell survival. The present study was performed to elucidate the role of ASC-2 in the regulation of insulin sensitivity. Although islet cells from 10-week-old ASC-2+/- mice secreted less insulin than wild-type islets, there was no significant difference in glucose tolerance between ASC-2+/- and wild-type mice. However, ASC-2+/- mice did show increased insulin sensitivity compared with wild-type mice in insulin tolerance tests. Consistently, the levels of phosphorylated Akt were higher in ASC-2+/- hepatocytes than in wild-type hepatocytes after insulin treatment. Moreover, decreases in phosphoenol pyruvate carboxykinase mRNA in refed mice were more prominent in ASC-2+/- livers than in wild-type livers. Interestingly, the expression levels of SOCS1 (suppressor of cytokine signaling 1) and SOCS3, well-known insulin signaling inhibitors, were decreased in ASC-2+/- hepatocytes and increased in ASC-2 overexpressing hepatocytes. Furthermore, ASC-2 was recruited to the promoter region of SOCS1 and potentiated the transcription by SREBP-1c (sterol regulatory element binding protein-1c). This transcription-activating function of ASC-2 was diminished by mutations of SREBP-1c-binding sites in the SOCS1 promoter. Taken together, these results suggest that ASC-2 negatively affects hepatic insulin sensitivity, at least in part, through induction of the insulin signaling inhibitors SOCS1 and SOCS3.

Key words: activating signal co-integrator-2 (ASC-2), co-activator, insulin sensitivity, suppressor of cytokine signaling 1(SOCS1), SOCS3, sterol regulatory element binding protein-1c (SREBP-1c).

 

1 These authors contributed equally to this work

2 To whom correspondence should be addressed (email swkim7@amc.seoul.kr).

Seung-Whan Kim-1

 

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