Regulation of Hepatic Gluconeogenesis by Nuclear Receptor Coactivator 6

Nuclear receptor coactivator 6 (NCOA6) is a transcriptional coactivator of nuclear receptors and other transcription factors. A general knockout mouse was previously shown to be embryonic lethal, but we here generated liver-specific knockout ( LKO) mice to investigate the metabolic function of NCOA6 in the liver. These LKO mice exhibited similar blood glucose and insulin levels to wild type but showed improvements in glucose tolerance, insulin sensitivity, and pyruvate tolerance. The decrease in glucose production from pyruvate in these LKO mice was consistent with the abrogation of the fasting-stimulated induction of gluconeogenic genes, phosphoenolpyruvate carboxykinase 1 ( ) and glucose-6-phosphatase ( ). The forskolin-stimulated inductions of and were also dramatically reduced in primary hepatocytes isolated from LKO mice, whereas the expression levels of other gluconeogenic gene regulators, including cAMP response element binding protein ( ), forkhead box protein O1 and peroxisome proliferator-activated receptor γ coactivator 1α, were unaltered in the LKO mouse livers. CREB phosphorylation via fasting or forskolin stimulation was normal in the livers and primary hepatocytes of the LKO mice. Notably, it was observed that CREB interacts with NCOA6. The transcriptional activity of CREB was found to be enhanced by NCOA6 in the context of and promoters. NCOA6-dependent augmentation was abolished in cAMP response element (CRE) mutant promoters of the and genes. Our present results suggest that NCOA6 regulates hepatic gluconeogenesis by modulating glucagon/cAMP-dependent gluconeogenic gene transcription through an interaction with CREB.