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Phosphoenolpyruvate carboxykinase is necessary for the integration of hepatic energy metabolism.

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.

Pubmed ID: 10938127


  • She P
  • Shiota M
  • Shelton KD
  • Chalkley R
  • Postic C
  • Magnuson MA


Molecular and cellular biology

Publication Data

September 21, 2000

Associated Grants

  • Agency: NIDDK NIH HHS, Id: DK42502

Mesh Terms

  • Alleles
  • Animals
  • Blood Glucose
  • Blotting, Northern
  • Blotting, Western
  • Crosses, Genetic
  • Female
  • Food Deprivation
  • Gene Targeting
  • Gluconeogenesis
  • Heterozygote
  • Kidney
  • Kinetics
  • Lipid Metabolism
  • Liver
  • Male
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Molecular Sequence Data
  • Phosphoenolpyruvate Carboxykinase (GTP)
  • RNA, Messenger
  • Time Factors
  • Up-Regulation