Abstract
Liver gluconeogenesis is essential to provide energy to glycolytic tissues during fasting periods. However, aberrant up-regulation of this metabolic pathway contributes to the progression of glucose intolerance in individuals with diabetes. Phosphoenolpyruvate carboxykinase (PEPCK) expression plays a critical role in the modulation of gluconeogenesis. Several pathways contribute to the regulation of PEPCK, including the nuclear receptor Rev-erbα and the histone deacetylase SIRT1. Deleted in breast cancer 1 (DBC1) is a nuclear protein that binds to and regulates both Rev-erbα and SIRT1 and, therefore, is a candidate to participate in the regulation of PEPCK. In this work, we provide evidence that DBC1 regulates glucose metabolism and the expression of PEPCK. We show that DBC1 levels decrease early in the fasting state. Also, DBC1 KO mice display higher gluconeogenesis in a normal and a high-fat diet. DBC1 absence leads to an increase in PEPCK mRNA and protein expression. Conversely, overexpression of DBC1 results in a decrease in PEPCK mRNA and protein levels. DBC1 regulates the levels of Rev-erbα, and manipulation of Rev-erbα activity or levels prevents the effect of DBC1 on PEPCK. In addition, Rev-erbα levels decrease in the first hours of fasting. Finally, knockdown of the deacetylase SIRT1 eliminates the effect of DBC1 knockdown on Rev-erbα levels and PEPCK expression, suggesting that the mechanism of PEPCK regulation is, at least in part, dependent on the activity of this enzyme. Our results point to DBC1 as a novel regulator of gluconeogenesis.
Highlights
Gluconeogenesis is an important physiological pathway in response to fasting and stress
We explored whether Deleted in breast cancer 1 (DBC1) is important for glucose metabolism and Phosphoenolpyruvate carboxykinase (PEPCK) regulation and the mechanisms involved in this process
We evaluated whether insulin release and insulin sensitivity were responsible for the differences in glucose tolerance between WT and DBC1 KO mice
Summary
Gluconeogenesis is an important physiological pathway in response to fasting and stress. Results: DBC1 regulates gluconeogenesis and PEPCK expression by a mechanism that is at least in part explained by the Rev-erb␣ and the deacetylase SIRT1. Significance: We aim to understand the molecular mechanisms of glucose metabolism and response to fasting. Several pathways contribute to the regulation of PEPCK, including the nuclear receptor Rev-erb␣ and the histone deacetylase SIRT1. Overexpression of DBC1 results in a decrease in PEPCK mRNA and protein levels. Rev-erb␣ levels decrease in the first hours of fasting. Knockdown of the deacetylase SIRT1 eliminates the effect of DBC1 knockdown on Rev-erb␣ levels and PEPCK expression, suggesting that the mechanism of PEPCK regulation is, at least in part, dependent on the activity of this enzyme. Our results point to DBC1 as a novel regulator of gluconeogenesis
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