title: Regulation of hepatic insulin sensitivity by activating signal co-integrator-2.
abstract: ASC-2 (activating signal co-integrator-2, also known as AIB3 and NCoA6) is a transcriptional co-activator and regulates insulin secretion and β-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-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 signalling inhibitors SOCS1 and SOCS3.
authors.affiliation: Department of Pharmacology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 138-736, South Korea.
authors.forename: Geun Hyang
authors.initials: GH
authors.lastname: Kim
authors.forename: Kyung Jin
authors.initials: KJ
authors.lastname: Lee
authors.forename: Gyun-Sik
authors.initials: GS
authors.lastname: Oh
authors.forename: Jin
authors.initials: J
authors.lastname: Yoon
authors.forename: Hae Won
authors.initials: HW
authors.lastname: Kim
authors.forename: Seung-Whan
authors.initials: SW
authors.lastname: Kim
mesh_terms: D000818:Animals; D001665:Binding Sites; D005215:Fasting; D005786:Gene Expression Regulation; D005943:Gluconeogenesis; D022781:Hepatocytes / Q000378:metabolism; D007328:Insulin / Q000502:physiology*; D007333:Insulin Resistance; D007515:Islets of Langerhans / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D056918:Nuclear Receptor Coactivators / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D007328:Insulin; C405683:Ncoa6 protein, mouse; D056918:Nuclear Receptor Coactivators; C491590:Socs1 protein, mouse; C491411:Socs3 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D051057:Proto-Oncogene Proteins c-akt