Regulation of Hepatic Fasting Response by PPARγ Coactivator-1α (PGC-1): Requirement for Hepatocyte Nuclear Factor 4α in Gluconeogenesis

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...

Full description

Saved in:
Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2003-04, Vol.100 (7), p.4012-4017
Main Authors: Rhee, James, Inoue, Yusuke, Yoon, J. Cliff, Puigserver, Pere, Fan, Melina, Gonzalez, Frank J., Spiegelman, Bruce M.
Format: Article
Language:eng
Subjects:
Biological Sciences
Fasting
Fatty acids
Gene expression regulation
Genes
Gluconeogenesis
Hepatocyte nuclear factors
Hepatocytes
Liver
Messenger RNA
Receptors
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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 phosphoenol-pyruvate 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.
ISSN:0027-8424
1091-6490