Deleted in breast cancer-1 (DBC1) regulates hepatic gluconeogenesis [Cell Biology]

January 10th, 2014 by Nin, V. S., Chini, C. C., Escande, C., Capellini, V., Chini, E. N.

Liver gluconeogenesis is essential to provide energy to glycolytic tissues during fasting periods. However, aberrant upregulation 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-erb and the histone deacetylase SIRT1. Deleted in Breast cancer-1 (DBC1) is a nuclear protein that binds to and regulates both Rev-erb 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-erb [alpha] and manipulation of Rev-erb [alpha] activity or levels prevents the effect of DBC1 on PEPCK. In addition, Rev-erb [alpha] levels decrease in the first hours of fasting. Finally, knock down of the deacetylase SIRT1 eliminates the effect of the DBC1 knockdown on Rev-erb [alpha] 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.