Insulin-Inducible SMILE Inhibits Hepatic Gluconeogenesis

• Published in: Diabetes (New York, N.Y.) Vol. 65; no. 1; pp. 62 - 73
• Main Authors: Lee, Ji-Min, Seo, Woo-Young, Han, Hye-Sook, Oh, Kyoung-Jin, Lee, Yong-Soo, Kim, Don-Kyu, Choi, Seri, Choi, Byeong Hun, Harris, Robert A, Lee, Chul-Ho, Koo, Seung-Hoi, Choi, Hueng-Sik
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.01.2016
• Subjects: Animals; Basic-Leucine Zipper Transcription Factors - drug effects; Basic-Leucine Zipper Transcription Factors - genetics; Basic-Leucine Zipper Transcription Factors - metabolism; Blotting, Western; Cell Line; Chromatin Immunoprecipitation; Diabetes; Diet, High-Fat; Eating - genetics; Gene Expression; Glucagon; Gluconeogenesis - genetics; Glucose; Hepatocyte Nuclear Factor 4 - genetics; Hepatocyte Nuclear Factor 4 - metabolism; Hepatocytes - drug effects; Hepatocytes - metabolism; Hyperglycemia; Hypoglycemic Agents - pharmacology; Insulin - pharmacology; Liver - drug effects; Liver - metabolism; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Knockout; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Polymerase Chain Reaction; Proto-Oncogene Proteins c-akt - genetics; Receptor, Insulin - genetics; Rodents; Transcription factors; Transcription Factors - genetics
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db15-0249

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.