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Insulin-Inducible SMILE Inhibits Hepatic Gluconeogenesis.
- Source :
- Diabetes; Jan2016, Vol. 65 Issue 1, p62-73, 12p, 1 Diagram, 7 Graphs
- Publication Year :
- 2016
-
Abstract
- The role of a glucagon/cAMP-dependent protein kinase-inducible coactivator PGC-1α signaling pathway is well characterized in hepatic gluconeogenesis. However, an opposing protein kinase B (PKB)/Akt-inducible corepressor signaling pathway is unknown. A previous report has demonstrated that small heterodimer partner-interacting leucine zipper protein (SMILE) regulates the nuclear receptors and transcriptional factors that control hepatic gluconeogenesis. Here, we show that hepatic SMILE expression was induced by feeding in normal mice but not in db/db and high-fat diet (HFD)-fed mice. Interestingly, SMILE expression was induced by insulin in mouse primary hepatocyte and liver. Hepatic SMILE expression was not altered by refeeding in liver-specific insulin receptor knockout (LIRKO) or PKB β-deficient (PKBβ(-/-)) mice. At the molecular level, SMILE inhibited hepatocyte nuclear factor 4-mediated transcriptional activity via direct competition with PGC-1α. Moreover, ablation of SMILE augmented gluconeogenesis and increased blood glucose levels in mice. Conversely, overexpression of SMILE reduced hepatic gluconeogenic gene expression and ameliorated hyperglycemia and glucose intolerance in db/db and HFD-fed mice. Therefore, SMILE is an insulin-inducible corepressor that suppresses hepatic gluconeogenesis. Small molecules that enhance SMILE expression would have potential for treating hyperglycemia in diabetes. [ABSTRACT FROM AUTHOR]
- Subjects :
- GLUCONEOGENESIS
INSULIN
GLUCAGON
CYCLIC-AMP-dependent protein kinase
HETERODIMERS
LABORATORY mice
INSULIN receptors
GENETIC overexpression
PROTEIN metabolism
ANIMAL experimentation
CELL lines
CELL receptors
DIET
EPITHELIAL cells
GENE expression
HYPOGLYCEMIC agents
INGESTION
LIVER
METABOLISM
MICE
POLYMERASE chain reaction
PROTEINS
TRANSCRIPTION factors
TRANSFERASES
WESTERN immunoblotting
PHARMACODYNAMICS
Subjects
Details
- Language :
- English
- ISSN :
- 00121797
- Volume :
- 65
- Issue :
- 1
- Database :
- Complementary Index
- Journal :
- Diabetes
- Publication Type :
- Academic Journal
- Accession number :
- 111925376
- Full Text :
- https://doi.org/10.2337/db15-0249