Regulation of hepatic fasting response by PPARγ coactivator-1α (PGC-1): Requirement for hepatocyte nuclear factor 4α in gluconeogenesis

The liver plays several critical roles in the metabolic adaptation to fasting. We have shown previously that the transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) is induced in fasted or diabetic liver and activates the entire program of gluconeogenesis. PGC-1α interacts with several nuclear receptors known to bind gluconeogenic promoters including the glucocorticoid receptor, hepatocyte nuclear factor 4α (HNF4α), and the peroxisome proliferator-activated receptors. However, the genetic requirement for any of these interactions has not been determined. Using hepatocytes from mice lacking HNF4α in the liver, we show here that PGC-1α completely loses its ability to activate key genes of gluconeogenesis such as phosphoenolpyruvate carboxykinase and glucose-6-phosphatase when HNF4α is absent. It is also shown that PGC-1α can induce genes of β-oxidation and ketogenesis in hepatocytes, but these effects do not require HNF4α. Analysis of the glucose-6-phosphatase promoter indicates a key role for HNF4α-binding sites that function robustly only when HNF4α is coactivated by PGC-1α. These data illustrate the involvement of PGC-1α in several aspects of the hepatic fasting response and show that HNF4α is a critical component of PGC-1α-mediated gluconeogenesis.