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Rhee, J. et al.

Regulation of hepatic fasting response by PPARgamma coactivator-1alpha (PGC-1): requirement for hepatocyte nuclear factor 4alpha 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 gamma coactivator-1alpha (PGC-1alpha) is induced in fasted or diabetic liver and activates the entire program of gluconeogenesis. PGC-1alpha interacts with several nuclear receptors known to bind gluconeogenic promoters including the glucocorticoid receptor, hepatocyte nuclear factor 4alpha (HNF4alpha), and the peroxisome proliferator-activated receptors. However, the genetic requirement for any of these interactions has not been determined. Using hepatocytes from mice lacking HNF4alpha in the liver, we show here that PGC-1alpha completely loses its ability to activate key genes of gluconeogenesis such as phosphoenolpyruvate carboxykinase and glucose-6-phosphatase when HNF4alpha is absent. It is also shown that PGC-1alpha can induce genes of beta-oxidation and ketogenesis in hepatocytes, but these effects do not require HNF4alpha. Analysis of the glucose-6-phosphatase promoter indicates a key role for HNF4alpha- binding sites that function robustly only when HNF4alpha is coactivated by PGC-1alpha. These data illustrate the involvement of PGC-1alpha in several aspects of the hepatic fasting response and show that HNF4alpha is a critical component of PGC-1alpha-mediated gluconeogenesis.[1]

References

Regulation of hepatic fasting response by PPARgamma coactivator-1alpha (PGC-1): requirement for hepatocyte nuclear factor 4alpha in gluconeogenesis. Rhee, J., Inoue, Y., Yoon, J.C., Puigserver, P., Fan, M., Gonzalez, F.J., Spiegelman, B.M. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]

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