| First Author | Nin V | Year | 2014 |
| Journal | J Biol Chem | Volume | 289 |
| Issue | 9 | Pages | 5518-27 |
| PubMed ID | 24415752 | Mgi Jnum | J:209502 |
| Mgi Id | MGI:5568011 | Doi | 10.1074/jbc.M113.512913 |
| Citation | Nin V, et al. (2014) Deleted in breast cancer 1 (DBC1) protein regulates hepatic gluconeogenesis. J Biol Chem 289(9):5518-27 |
| abstractText | 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-erbalpha and the histone deacetylase SIRT1. Deleted in breast cancer 1 (DBC1) is a nuclear protein that binds to and regulates both Rev-erbalpha 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-erbalpha, and manipulation of Rev-erbalpha activity or levels prevents the effect of DBC1 on PEPCK. In addition, Rev-erbalpha levels decrease in the first hours of fasting. Finally, knockdown of the deacetylase SIRT1 eliminates the effect of DBC1 knockdown on Rev-erbalpha 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. |
