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Molecular and Cellular Biology, September 2000, p. 6508-6517, Vol. 20, No. 17
Department of Molecular Physiology and
Biophysics, Vanderbilt University School of Medicine, Nashville,
Tennessee 37232
Received 29 March 2000/Accepted 5 May 2000
We used an allelogenic Cre/loxP gene targeting strategy
in mice to determine the role of cytosolic phosphoenolpyruvate
carboxykinase (PEPCK) in hepatic energy metabolism. Mice that lack this
enzyme die within 3 days of birth, while mice with at least a 90%
global reduction of PEPCK, or a liver-specific knockout of PEPCK, are viable. Surprisingly, in both cases these animals remain euglycemic after a 24-h fast. However, mice without hepatic PEPCK develop hepatic
steatosis after fasting despite up-regulation of a variety of genes
encoding free fatty acid-oxidizing enzymes. Also, marked alterations in
the expression of hepatic genes involved in energy metabolism occur in
the absence of any changes in plasma hormone concentrations. Given that
a ninefold elevation of the hepatic malate concentration occurs in the
liver-specific PEPCK knockout mice, we suggest that one or more
intermediary metabolites may directly regulate expression of the
affected genes. Thus, hepatic PEPCK may function more as an integrator
of hepatic energy metabolism than as a determinant of gluconeogenesis.
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Phosphoenolpyruvate Carboxykinase Is Necessary for
the Integration of Hepatic Energy Metabolism
*
Corresponding author. Mailing address: 702 Light Hall,
Vanderbilt University School of Medicine, Nashville, TN 37232-0615. Phone: (615) 322-7006. Fax: (615) 322-7236. E-mail:
mark.magnuson{at}mcmail.vanderbilt.edu.
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