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 journalArticlepeer-review

23 Citations (Scopus)


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
Pages (from-to)62-73
Number of pages12
Issue number1
Publication statusPublished - 2016 Jan

Bibliographical note

Publisher Copyright:
© 2016 by the American Diabetes Association.

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism


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