Endoplasmic Reticulum Stress Inhibits STAT3-Dependent Suppression of Hepatic Gluconeogenesis via Dephosphorylation and Deacetylation
- Kumi Kimura1,
- Tomoko Yamada1,2,
- Michihiro Matsumoto3,
- Yoshiaki Kido4,5,
- Tetsuya Hosooka4,
- Shun-ichiro Asahara4,
- Tomokazu Matsuda4,
- Tsuguhito Ota1,
- Hiroshi Watanabe6,
- Yoshimichi Sai2,
- Kenichi Miyamoto2,
- Shuichi Kaneko7,
- Masato Kasuga3 and
- Hiroshi Inoue1⇓
- 1Frontier Science Organization, Kanazawa University, Kanazawa, Ishikawa, Japan
- 2Department of Medicinal Informatics, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
- 3Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
- 4Department of Internal Medicine, Division of Diabetes, Metabolism, and Endocrinology, Kobe University Graduate School of Medicine, Kobe, Japan
- 5Department of Biophysics, Division of Medical Chemistry, Kobe University Graduate School of Health Sciences, Kobe, Japan
- 6Brand's Brain Research Centre, Cerebos Pacific Limited, Singapore
- 7Department of Disease Control and Homeostasis, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
- Corresponding author: Hiroshi Inoue, .
In the liver, signal transducer and activator of transcription 3 (STAT3) plays an important role in the suppression of gluconeogenic enzyme expression. While obesity-associated endoplasmic reticulum (ER) stress has been shown to increase hepatic gluconeogenic enzyme expression, the role of ER stress in STAT3-dependent regulation of such expression is unclear. The current study aimed to elucidate the effect of ER stress on the STAT3-dependent regulation of hepatic gluconeogenic enzyme expression. Genetically obese/diabetic db/db mice and db/db mouse–derived isolated hepatocytes were used as ER stress models. A tyrosine phosphatase inhibitor, a deacetylation inhibitor, and an acetylated mutant of STAT3 were used to examine the effect of ER stress on hepatic STAT3 action. ER stress inhibited STAT3-dependent suppression of gluconeogenic enzyme gene expression by suppressing hepatic Janus kinase (JAK)2 and STAT3 phosphorylation. A tyrosine phosphatase inhibitor restored ER stress–induced suppression of JAK2 phosphorylation but exhibited no improving effect on suppressed STAT3 phosphorylation. STAT3 acetylation is known to correlate with its phosphorylation. ER stress also decreased STAT3 acetylation. An acetylated mutant of STAT3 was resistant to ER stress–induced inhibition of STAT3-phosphorylation and STAT3-dependent suppression of hepatic gluconeogenic enzyme gene expression in vitro and in vivo. Trichostatin A, a histone deacetylase (HDAC) inhibitor, ameliorated ER stress–induced inhibition of STAT3 acetylation and phosphorylation. The current study revealed that ER stress inhibits STAT3-dependent suppression of hepatic gluconeogenic enzymes via JAK2 dephosphorylation and HDAC-dependent STAT3 deacetylation, playing an important role in the increase of hepatic glucose production in obesity and diabetes.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db10-1684/-/DC1.
- Received December 8, 2010.
- Accepted October 6, 2011.
- © 2012 by the American Diabetes Association.
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