From the Department of Anesthesiology and Kogod Center on Aging, Mayo Clinic, Rochester, Minnesota 55905.
J Biol Chem. 2014 Feb 28;289(9):5518-27. doi: 10.1074/jbc.M113.512913. Epub 2014 Jan 10.
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.
肝脏糖异生对于禁食期间为糖酵解组织提供能量至关重要。然而，这种代谢途径的异常上调导致糖尿病患者的葡萄糖耐量下降。磷酸烯醇丙酮酸羧激酶（PEPCK）的表达在调节糖异生中起着关键作用。有几条途径有助于调节 PEPCK，包括核受体 Rev-erbα 和组蛋白去乙酰化酶 SIRT1。乳腺癌缺失蛋白 1（DBC1）是一种核蛋白，可与 Rev-erbα 和 SIRT1 结合并调节它们，因此是参与调节 PEPCK 的候选蛋白。在这项工作中，我们提供了证据表明 DBC1 调节葡萄糖代谢和 PEPCK 的表达。我们表明，禁食早期 DBC1 水平下降。此外，DBC1KO 小鼠在正常和高脂肪饮食中表现出更高的糖异生。DBC1 的缺失导致 PEPCK mRNA 和蛋白表达增加。相反，DBC1 的过表达导致 PEPCK mRNA 和蛋白水平降低。DBC1 调节 Rev-erbα 的水平，并且操纵 Rev-erbα 的活性或水平可以防止 DBC1 对 PEPCK 的影响。此外，禁食的最初几个小时 Rev-erbα 水平下降。最后，敲低去乙酰化酶 SIRT1 消除了 DBC1 敲低对 Rev-erbα 水平和 PEPCK 表达的影响，表明 PEPCK 调节的机制至少部分依赖于该酶的活性。我们的结果表明 DBC1 是糖异生的一种新的调节因子。
