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J Biol Chem, Vol. 275, Issue 19, 14717-14721, May 12, 2000
From the Department of Molecular Physiology and Biophysics,
Vanderbilt University Medical School,
Nashville, Tennessee, 37232-0615
Glucocorticoids stimulate gluconeogenesis by
increasing the rate of transcription of genes that encode gluconeogenic
enzymes such as phosphoenolpyruvate carboxykinase (PEPCK) and
glucose-6-phosphatase. Previous studies have shown that hepatic nuclear
factor 3 (HNF3) is required as an accessory factor for several
glucocorticoid-stimulated genes, including PEPCK. Here, we show that
adenovirus-mediated expression of an HNF3
The Molecular Physiology of Hepatic Nuclear Factor 3 in the
Regulation of Gluconeogenesis*
,
protein with a deleted
C-terminal transactivation domain (HNF3
C) reduces the
glucocorticoid-induced expression of the PEPCK and
glucose-6-phosphatase genes in H4IIE hepatoma cells. Furthermore,
expression of this truncated HNF3 protein results in a proportionate
reduction of glucocorticoid-stimulated glucose production from lactate
and pyruvate in these cells. The expression of HNF3N, in which
the N-terminal transactivation domain is deleted, does not exhibit any
of these effects. These results provide direct evidence that members of
the HNF3 family are required for proper regulation of hepatic
gluconeogenesis. Modulation of the function of the HNF3 family of
proteins might be used to reduce the excessive hepatic production of
glucose that is an important pathophysiologic feature of diabetes mellitus.
*
This work was supported by National Institutes of Health
Grants DK 20593 (to the Vanderbilt Diabetes Research and Training Center), DK 35107, and GM 07347 (to the Vanderbilt Medical Scientist Training Program).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Present address: Dept. of Cellular and Molecular Pharmacology,
University of California, San Francisco, CA 94143.
§
Present address: Dept. of Biochemistry and Molecular Biology, LSU
Medical Center, New Orleans, LA 70112.
¶
Present address: Dept. of Biochemistry, University of Dundee,
Dundee DD1 4HN, UK.
To whom correspondence should be addressed. Tel.:
615-322-7004; Fax: 615-322-7236; E-mail:
Daryl.Granner@mcmail.vanderbilt.edu.
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