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PMID: 12651943 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Regulation of hepatic fasting response by PPARgamma coactivator-1alpha (PGC-1): requirement for hepatocyte nuclear factor 4alpha in gluconeogenesis.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 100 ·No. 7 ·2003-04-01 ·Pages 4012-7

Rhee J, Inoue Y, Yoon JC, Puigserver P, Fan M, Gonzalez FJ, Spiegelman BM

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.

MeSH Terms
Adenoviridae/genetics Animals Basic Helix-Loop-Helix Leucine Zipper Transcription Factors Cells, Cultured DNA-Binding Proteins/metabolism Fasting/physiology Genetic Vectors Gluconeogenesis/genetics,physiology Hepatocyte Nuclear Factor 4 Hepatocytes/cytology,physiology Liver/physiology Mice Mice, Knockout Phosphoproteins/deficiency,genetics,metabolism Receptors, Cytoplasmic and Nuclear/physiology Recombinant Proteins/metabolism Time Factors Transcription Factors/deficiency,genetics,metabolism,physiology Transfection
Chemicals
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors DNA-Binding Proteins Hepatocyte Nuclear Factor 4 Hnf4a protein, mouse Phosphoproteins Receptors, Cytoplasmic and Nuclear Recombinant Proteins Tcfl4 protein, mouse Transcription Factors peroxisome-proliferator-activated receptor-gamma coactivator-1
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Rhee James
Dana Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Inoue Yusuke
Yoon J Cliff
Puigserver Pere
Fan Melina
Gonzalez Frank J
Spiegelman Bruce M
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0730870100
Published
2003-04-01
Epub
2003-00-21
Pages
4012-7
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC153039
Subset
IM
Grants
NIDDK NIH HHS · R01 DK061562 · United States
NIDDK NIH HHS · DK 61562 · United States
External Links
PubMed source DOI: 10.1073/pnas.0730870100 PMC Full Text View journal details
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