PEPCK-C reexpression in the liver counters neonatal hypoglycemia in Pck1 del/del mice, unmasking role in non-gluconeogenic tissues

J Physiol Biochem. 2017 Feb;73(1):89-98. doi: 10.1007/s13105-016-0528-y. Epub 2016 Oct 26.

Abstract

Whole body cytosolic phosphoenolpyruvate carboxykinase knockout (PEPCK-C KO) mice die early after birth with profound hypoglycemia therefore masking the role of PEPCK-C in adult, non-gluconeogenic tissues where it is expressed. To investigate whether PEPCK-C deletion in the liver was critically responsible for the hypoglycemic phenotype, we reexpress this enzyme in the liver of PEPCK-C KO pups by early postnatal administration of PEPCK-C-expressing adenovirus. This maneuver was sufficient to partially rescue hypoglycemia and allow the pups to survive and identifies the liver as a critical organ, and hypoglycemia as the critical pathomechanism, leading to early postnatal death in the whole-body PEPCK-C knockout mice. Pathology assessment of survivors also suggest a possible role for PEPCK-C in lung maturation and muscle metabolism.

Keywords: Gluconeogenesis; Hepatic lipidosis; KO; Liver; Neonatal hypoglycemia; PEPCK.

MeSH terms

  • Animals
  • Animals, Newborn
  • Brain / enzymology
  • Brain / metabolism
  • Brain / pathology
  • Carbohydrate Metabolism, Inborn Errors / enzymology
  • Carbohydrate Metabolism, Inborn Errors / physiopathology
  • Carbohydrate Metabolism, Inborn Errors / therapy
  • Carbohydrate Metabolism, Inborn Errors / veterinary*
  • Crosses, Genetic
  • Gene Transfer Techniques
  • Gluconeogenesis
  • Heterozygote
  • Hypoglycemia / etiology
  • Hypoglycemia / metabolism
  • Hypoglycemia / pathology
  • Hypoglycemia / prevention & control*
  • Lipid Droplets / metabolism
  • Lipid Droplets / pathology
  • Lipid Metabolism
  • Lipidoses / etiology
  • Liver / enzymology*
  • Liver / metabolism
  • Liver / pathology
  • Liver Diseases / enzymology
  • Liver Diseases / physiopathology
  • Liver Diseases / therapy
  • Liver Diseases / veterinary*
  • Lung / enzymology
  • Lung / metabolism*
  • Lung / pathology
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscle, Skeletal / enzymology
  • Muscle, Skeletal / metabolism*
  • Muscle, Skeletal / pathology
  • Neurons / enzymology
  • Neurons / metabolism
  • Neurons / pathology
  • Phosphoenolpyruvate Carboxykinase (GTP) / deficiency*
  • Phosphoenolpyruvate Carboxykinase (GTP) / genetics
  • Phosphoenolpyruvate Carboxykinase (GTP) / metabolism*
  • Phosphoenolpyruvate Carboxykinase (GTP) / therapeutic use
  • Recombinant Proteins / metabolism

Substances

  • Recombinant Proteins
  • Phosphoenolpyruvate Carboxykinase (GTP)

Supplementary concepts

  • Phosphoenolpyruvate carboxykinase deficiency