Regulation of hepatic fasting response by PPAR coactivator-1 (PGC-1): Requirement for hepatocyte nuclear factor 4 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 coactivator-1 (PGC-1 ) is induced in fasted or diabetic liver and activates the entire program of gluconeogenesis. PGC-1 interacts with several nuclear receptors known to bind gluconeogenic promoters including the glucocorticoid receptor, hepatocyte nuclear factor 4 (HNF4 ), and the peroxisome proliferator-activated receptors. However, the genetic requirement for any of these interactions has not been determined. Using hepatocytes from mice lacking HNF4 in the liver, we show here that PGC-1 completely loses its ability to activate key genes of gluconeogenesis such as phosphoenolpyruvate carboxykinase and glucose-6-phosphatase when HNF4 is absent. It is also shown that PGC-1 can induce genes of -oxidation and ketogenesis in hepatocytes, but these effects do not require HNF4 . Analysis of the glucose-6-phosphatase promoter indicates a key role for HNF4 -binding sites that function robustly only when HNF4 is coactivated by PGC-1 . These data illustrate the involvement of PGC-1 in several aspects of the hepatic fasting response and show that HNF4 is a critical component of PGC-1 -mediated gluconeogenesis.