title: B-cell translocation gene 2 regulates hepatic glucose homeostasis via induction of orphan nuclear receptor Nur77 in diabetic mouse model.
abstract: 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.
authors.affiliation: Department of Physiology, Keimyung University School of Medicine, Daegu, Republic of Korea.
authors.forename: Yong Deuk
authors.initials: YD
authors.lastname: Kim
authors.affiliation: Neuroscience Section, Department of Pediatrics, Papé Family Pediatric Research Institute, Oregon Health and Science University, Portland, OR.
authors.forename: Sun-Gyun
authors.initials: SG
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan, Republic of Korea.
authors.forename: Seung-Lark
authors.initials: SL
authors.lastname: Hwang
authors.affiliation: School of Biological Sciences and Technology, National Creative Research Initiatives Center for Nuclear Receptor Signals, Hormone Research Center, Chonnam National University, Gwangju, Republic of Korea.
authors.forename: Hueng-Sik
authors.initials: HS
authors.lastname: Choi
authors.affiliation: Department of Physiology, Keimyung University School of Medicine, Daegu, Republic of Korea.
authors.forename: Jae-Hoon
authors.initials: JH
authors.lastname: Bae
authors.affiliation: Department of Physiology, Keimyung University School of Medicine, Daegu, Republic of Korea ssim73@kmu.ac.kr dksong@kmu.ac.kr.
authors.forename: Dae-Kyu
authors.initials: DK
authors.lastname: Song
authors.affiliation: Department of Physiology, Keimyung University School of Medicine, Daegu, Republic of Korea ssim73@kmu.ac.kr dksong@kmu.ac.kr.
authors.forename: Seung-Soon
authors.initials: SS
authors.lastname: Im
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism*; D005786:Gene Expression Regulation; D005943:Gluconeogenesis; D006706:Homeostasis; D017874:Immediate-Early Proteins / Q000235:genetics / Q000494:pharmacology*; D050417:Insulin-Secreting Cells / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000187:drug effects / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D015533:Transcriptional Activation / Q000187:drug effects; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000494:pharmacology*; D015854:Up-Regulation
chemical_list: D001786:Blood Glucose; C489435:Btg2 protein, mouse; D017874:Immediate-Early Proteins; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D025521:Tumor Suppressor Proteins