Phosphoenolpyruvate Carboxykinase Is Necessary for the Integration of Hepatic Energy Metabolism

Abstract

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.

ACKNOWLEDGMENTS

We thank D. Wasserman, P. Flakoll, Y. Fujimoto, E. P. Donahue, M.-Y. Zhu, and J. Lindner for help and advice in performing these studies, and we thank A. D. Cherrington and D. K. Granner for reading the manuscript and providing comments. We are also indebted to A. Saha (Boston University) for measuring malonyl-CoA and to D. Kelly (Washington University) for providing cDNA for CYP4A3, CYP4A1, and MCAD.

This study was supported by funding from the National Institutes of Health (grant DK42502). P. She is a recipient of a JDFI postdoctoral fellowship.