Phosphoenolpyruvate carboxykinase is necessary for the integration of hepatic energy metabolism

We used an allelogenic Cre/loxP gene targeting strategy in mice to determin e the role of cytosolic phosphoenolpyruvate carboxykinase (PEPCK) in hepati c 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-speci fic knockout of PEPCK, are viable. Surprisingly, in both cases these animal s 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 fi ee fatty acid-oxidizing enzymes. Also, marked alterati ons 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 live r-specific PEPCK knockout mice, we suggest that one or more intermediary me tabolites may directly regulate expression of the affected genes. Thus, hep atic PEPCK may function more as an integrator of hepatic energy metabolism than as a determinant of gluconeogenesis.