A single extra copy of Down syndrome critical region 1-4 results in impaired hepatic glucose homeostasis.

Abstract

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.

• Authors: Dong Soo Seo, Gia Cac Chau, Kwan-Hyuck Baek, Sung Hee Um
• Journal: Molecular metabolism (Mol Metab) Vol. 21 Pg. 82-89 (03 2019) ISSN: 2212-8778 [Electronic] Germany
• PMID: 30583978 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 The Authors. Published by Elsevier GmbH.. All rights reserved.

Chemical References

• Calcineurin Inhibitors
• Cyclic AMP Response Element-Binding Protein
• Cyclosporine
• Glucose

Topics

• Animals
• Calcineurin Inhibitors (pharmacology)
• Cyclic AMP Response Element-Binding Protein (metabolism)
• Cyclosporine (pharmacology)
• Diet, High-Fat (adverse effects)
• Down Syndrome (genetics, metabolism)
• Fasting (metabolism)
• Gene Expression (drug effects)
• Gluconeogenesis (drug effects)
• Glucose (metabolism)
• HEK293 Cells
• Hepatocytes (metabolism)
• Homeostasis
• Humans
• Liver (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Obese
• Mice, Transgenic
• Obesity (etiology, metabolism)
• Phosphorylation
• Transfection
• Trisomy (genetics)