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

Jana Semakova; Petra Hyroššová; Andrés Méndez-Lucas; Ernest Cutz; Jordi Bermudez; Shawn Burgess; Soledad Alcántara; José C Perales

doi:10.1007/s13105-016-0528-y

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.

Authors

Jana Semakova¹, Petra Hyroššová¹, Andrés Méndez-Lucas¹, Ernest Cutz², Jordi Bermudez¹, Shawn Burgess³, Soledad Alcántara⁴, José C Perales^{5

6}

Affiliations

¹ Department of Physiological Sciences, Faculty of Medicine, University of Barcelona, L'Hospitalet del Llobregat, Barcelona, Spain.
² Division of Pathology, Department of Pediatric Laboratory Medicine, The Hospital for Sick Children and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
³ Advanced Imaging Research Center and Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
⁴ Department of Experimental Pathology and Therapeutics, Faculty of Medicine, University of Barcelona, L'Hospitalet del Llobregat, Barcelona, Spain.
⁵ Department of Physiological Sciences, Faculty of Medicine, University of Barcelona, L'Hospitalet del Llobregat, Barcelona, Spain. jperales@ub.edu.
⁶ IDIBELL, L'Hospitalet del Llobregat, Barcelona, Spain. jperales@ub.edu.

PMID: 27785616
DOI: 10.1007/s13105-016-0528-y

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