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Molecular and Cellular Biology, September 2000, p. 6508-6517, Vol. 20, No. 17
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

Pengxiang She, Masakazu Shiota, Kathy D. Shelton, Roger Chalkley, Catherine Postic, and Mark A. Magnuson*

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.

* 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.

Molecular and Cellular Biology, September 2000, p. 6508-6517, Vol. 20, No. 17
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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