Insulin-Inducible SMILE inhibits hepatic gluconeogenesis

Ji Min Lee, Woo Young Seo, Hye Sook Han, Kyoung Jin Oh, Yong Soo Lee, Don Kyu Kim, Seri Choi, Byeong Hun Choi, Robert A. Harris, Chul Ho Lee, Seung Hoi Koo, Hueng Sik Choi

Research output: Contribution to journalArticle

11 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)62-73
Number of pages12
JournalDiabetes
Volume65
Issue number1
DOIs
StatePublished - Jan 2016

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ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Lee, J. M., Seo, W. Y., Han, H. S., Oh, K. J., Lee, Y. S., Kim, D. K., Choi, S., Choi, B. H., Harris, R. A., Lee, C. H., Koo, S. H., & Choi, H. S. (2016). Insulin-Inducible SMILE inhibits hepatic gluconeogenesis. Diabetes, 65(1), 62-73. https://doi.org/10.2337/db15-0249