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- Title
Regulation of hepatic insulin sensitivity by activating signal co-integrator-2.
- Authors
KIM, Geun Hyang; LE, Kyung Jin; OH, Gyun-Sik; YOON, Jin; KIM, Hae Won; KIM, Seung-Whan
- Abstract
ASC-2 (activating signal co-integrator-2, also known as AIB3 and NCoA6) is a transcriptional co-activator and regulates insulin secretion and ß-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 signalling 1) and SOCS3, well-known insulin signalling inhibitors, were decreased in ASC-2 /- hepatocytes and increased in ASC-2- overexpressing hepatocytes. Furthermore, ASC-2was 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 signalling inhibitors SOCS1 and SOCS3.
- Subjects
INSULIN; LIVER cells; STEROL regulatory element-binding proteins; CYTOKINES; GLUCOSE tolerance tests; PROMOTERS (Genetics); BINDING sites; NUCLEAR receptors (Biochemistry)
- Publication
Biochemical Journal, 2012, Vol 447, Issue 3, p437
- ISSN
0264-6021
- Publication type
Academic Journal
- DOI
10.1042/BJ20120861