A single extra copy of Down syndrome critical region 1–4 results in impaired hepatic glucose homeostasis
| Autor: | Kwan-Hyuck Baek, Dong Soo Seo, Gia Cac Chau, Sung Hee Um |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine InsP3Rs inositol-1 4 5-triphosphate receptors DSCR1-4 DSCR1-4 Down syndrome critical region1-4 Gene Expression Mice Obese Trisomy Type 2 diabetes Energy homeostasis Mice 0302 clinical medicine Cyclosporin a Homeostasis Glucose homeostasis Phosphorylation Cyclic AMP Response Element-Binding Protein Calcineurin Diabetes Fasting Liver NFAT nuclear factor of activated T cells Cyclosporine CsA cyclosporine A Genetically modified mouse lcsh:Internal medicine medicine.medical_specialty Calcineurin Inhibitors NIK nuclear factor-κB-inducing kinase Mice Transgenic 030209 endocrinology & metabolism Biology Diet High-Fat Transfection Brief Communication 03 medical and health sciences Diabetes mellitus Internal medicine medicine Animals Humans Obesity PTDM posttransplantation diabetes lcsh:RC31-1245 Molecular Biology Gluconeogenesis Cell Biology GSK3β glycogen synthase kinase-3 beta medicine.disease Mice Inbred C57BL Hepatic glucose homeostasis Glucose HEK293 Cells 030104 developmental biology Endocrinology Hepatocytes Down Syndrome |
| Zdroj: | Molecular Metabolism Molecular Metabolism, Vol 21, Iss, Pp 82-89 (2019) |
| ISSN: | 2212-8778 |
| DOI: | 10.1016/j.molmet.2018.12.002 |
| Popis: | Objectives During fasting, hepatic gluconeogenesis is induced to maintain energy homeostasis. Moreover, abnormal dysregulation of hepatic glucose production is commonly observed in type 2 diabetes. However, the signaling components controlling hepatic glucose production to maintain normal glucose levels are not fully understood. Here, we examined the physiological role of Down syndrome critical region 1–4 (DSCR1-4), an endogenous calcineurin signaling inhibitor in the liver that mediates metabolic adaptation to fasting. Methods We assessed the effect of cyclosporine A, an inhibitor of calcineurin signaling on gluconeogenic gene expression in primary hepatocytes. DSCR1-4 expression was examined in diet- and genetically-induced mouse models of obesity. We also investigated the metabolic phenotype of a single extra copy of DSCR1-4 in transgenic mice and how DSCR1-4 regulates glucose homeostasis in the liver. Results Treatment with cyclosporin A increased hepatic glucose production and gluconeogenic gene expression. The expression of DSCR1-4 was induced by refeeding and overexpressed in obese mouse livers. Moreover, transgenic mice with a single extra copy of DSCR1-4 exhibited pyruvate intolerance and impaired glucose homeostasis. Mechanistically, DSCR1-4 overexpression increased phosphorylation of the cAMP response element-binding protein, which led to elevated expression levels of gluconeogenic genes and, thus, enhanced hepatic glucose production during fasting. Conclusion A single extra copy of DSCR1-4 results in dysregulated hepatic glucose homeostasis and pyruvate intolerance. Our findings suggest that nutrient-sensitive DSCR1-4 is a novel target for controlling hepatic gluconeogenesis in diabetes. Highlights • DSCR1 mRNA and protein levels are increased in livers upon nutrient availability. • DSCR1-4 is overexpressed in diet- or genetically induced obesity. • DSCR1-4 trisomy mice exhibit impaired glucose homeostasis and pyruvate intolerance. • Trisomy of DSCR1-4 leads to increased hepatic glucose production. |
| Databáze: | OpenAIRE |
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