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Peroxisome Proliferator-Activated Receptor Coactivator-1, as a Transcription Amplifier, Is Not Essential for Basal and Hormone-Induced Phosphoenolpyruvate Carboxykinase Gene Expression

Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine and Veteran’s Affairs Medical Center, Nashville, Tennessee 37232-0615

Address all correspondence and requests for reprints to: Daryl K. Granner, Department of Molecular Physiology and Biophysics, 707 Light Hall, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0615. E-mail: daryl.granner{at}vanderbilt.edu.

Phosphoenolpyruvate carboxykinase (PEPCK) catalyzes the initial step in hepatic gluconeogenesis. In the fasted state, PEPCK gene expression is activated by glucagon (via cAMP) and glucocorticoids. Peroxisome proliferator-activated receptor coactivator 1 (PGC-1) plays an important role in energy homeostasis and is considered to be a key regulator of hepatic gluconeogenesis in response to fasting. It is not clear whether PGC-1 is obligatory for the activation of the transcription program of gluconeogenic genes, or whether it amplifies an existing process. H4IIE hepatoma cells were used to address this key point. These cells respond appropriately to all of the hormones involved in the regulation of gluconeogenic genes, yet they are devoid of PGC-1. Also, these hormone responses occur in the absence of ongoing protein synthesis, so the necessary complement of transcription factors exists in untreated cells. However, exogenous expression of PGC-1 in these cells does enhance basal and hormone-induced expression of the PEPCK and glucose-6-phosphatase genes. Mutational analyses of the PEPCK gene promoter reveal that one element in the PEPCK gene promoter, glucocorticoid accessory factor 3, which binds chicken ovalbumin upstream promoter-transcription factor, is of particular importance. Taken together, these data suggest that, under chronic fasting conditions, i.e. when high levels of cAMP and glucocorticoids induce PGC-1 expression, this coactivator markedly amplifies PEPCK gene expression and gluconeogenesis.

NURSA Molecule Pages Link:

Nuclear Receptors:   RXRα  |  COUP-TFI  |  AR

Coregulators:   PGC-1

Ligands:   Dexamethasone

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