Insulin-Inducible SMILE Inhibits Hepatic Gluconeogenesis.
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.
National Creative Research Initiatives Center for Nuclear Receptor Signals and Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea.
Ji-Min
JM
Lee
Division of Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea.
Woo-Young
WY
Seo
Division of Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea.
Hye-Sook
HS
Han
Division of Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea.
Kyoung-Jin
KJ
Oh
National Creative Research Initiatives Center for Nuclear Receptor Signals and Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea.
Yong-Soo
YS
Lee
National Creative Research Initiatives Center for Nuclear Receptor Signals and Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea.
Don-Kyu
DK
Kim
Division of Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea.
Seri
S
Choi
Division of Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea.
Byeong Hun
BH
Choi
Richard Roudebush Veterans Affairs Medical Center and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN.
Robert A
RA
Harris
Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
Chul-Ho
CH
Lee
Division of Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea hsc@chonnam.ac.kr koohoi@korea.ac.kr.
Seung-Hoi
SH
Koo
National Creative Research Initiatives Center for Nuclear Receptor Signals and Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea hsc@chonnam.ac.kr koohoi@korea.ac.kr.
Hueng-Sik
HS
Choi
D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D059305:Diet, High-Fat; D004435:Eating / Q000235:genetics*; D015870:Gene Expression; D005934:Glucagon; D005943:Gluconeogenesis / Q000235:genetics*; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics* / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016133:Polymerase Chain Reaction; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D011972:Receptor, Insulin / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics
D050976:Basic-Leucine Zipper Transcription Factors; D051557:Hepatocyte Nuclear Factor 4; D007004:Hypoglycemic Agents; D007328:Insulin; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; C570109:SMILE protein, mouse; D014157:Transcription Factors; D005934:Glucagon; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt