B-Cell Translocation Gene 2 Regulates Hepatic Glucose Homeostasis via Induction of Orphan Nuclear Receptor Nur77 in Diabetic Mouse Model
- Yong Deuk Kim1,
- Sun-Gyun Kim2,
- Seung-Lark Hwang3,
- Hueng-Sik Choi4,
- Jae-Hoon Bae1,
- Dae-Kyu Song1⇑ and
- Seung-Soon Im1⇑
- 1Department of Physiology, Keimyung University School of Medicine, Daegu, Republic of Korea
- 2Neuroscience Section, Department of Pediatrics, Papé Family Pediatric Research Institute, Oregon Health and Science University, Portland, OR
- 3College of Pharmacy, Yeungnam University, Gyeongsan, Republic of Korea
- 4School of Biological Sciences and Technology, National Creative Research Initiatives Center for Nuclear Receptor Signals, Hormone Research Center, Chonnam National University, Gwangju, Republic of Korea
- Corresponding authors: Seung-Soon Im, , and Dae-Kyu Song, .
B-cell translocation gene 2 (BTG2) is a member of an emerging gene family that is involved in cellular functions. In this study, we demonstrate that BTG2 regulates glucose homeostasis via upregulation of Nur77 in diabetic mice. Hepatic BTG2 gene expression was elevated by fasting and forskolin. Overexpression of Btg2 increased the expression of hepatic gluconeogenic genes and blood glucose output and subsequently impaired glucose and insulin tolerance. Upregulation of the transcriptional activity of Nur77, gluconeogenic genes, and glucose production by forskolin was observed by Btg2 transduction, but not in Btg2 knockdown. BTG2-stimulated glucose production and glucose-6-phosphatase promoter activity were attenuated by dominant-negative Nur77. Coimmunoprecipitation and chromatin immunoprecipitation assays showed that BTG2 induced Nur77 occupancy on the glucose-6-phosphatase promoter via a physical interaction. Btg2 gene expression was increased in streptozotocin-treated and db/db mice. Finally, impairment of glucose homeostasis, such as the increase of blood glucose, glucose intolerance, and insulin intolerance, was elevated in diabetic mice, whereas this phenomenon was abolished in knockdown of Btg2. Together, these data suggest that BTG2 participates in the regulation of hepatic glucose homeostasis, which means that BTG2 might serve as a potential therapeutic target for combating metabolic dysfunction.
- Received September 5, 2013.
- Accepted February 5, 2014.
- © 2014 by the American Diabetes Association.
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