Dataset Information

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.

SUBMITTER: Seo DS

PROVIDER: S-EPMC6407364 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Publications

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

Seo Dong Soo DS Chau Gia Cac GC Baek Kwan-Hyuck KH Um Sung Hee SH

Molecular metabolism 20181205

<h4>Objectives</h4>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 ...[more]

PMID: 30583978

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Dataset Information

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

Objectives

Methods

Results

Conclusion

Publications

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

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