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  • Title: Regulation of hepatic fasting response by PPARgamma coactivator-1alpha (PGC-1): requirement for hepatocyte nuclear factor 4alpha in gluconeogenesis.
    Author: Rhee J, Inoue Y, Yoon JC, Puigserver P, Fan M, Gonzalez FJ, Spiegelman BM.
    Journal: Proc Natl Acad Sci U S A; 2003 Apr 01; 100(7):4012-7. PubMed ID: 12651943.
    Abstract:
    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.
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