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

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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.

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Acknowledgments

We thank the Research Support Services from the Biology Unit of Bellvitge (University of Barcelona) for their technical assistance.

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Authors and Affiliations

  1. Department of Physiological Sciences, Faculty of Medicine, University of Barcelona, L’Hospitalet del Llobregat, Barcelona, Spain

    Jana Semakova, Petra Hyroššová, Andrés Méndez-Lucas, Jordi Bermudez & José C. Perales

  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

    Ernest Cutz

  3. Advanced Imaging Research Center and Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Shawn Burgess

  4. Department of Experimental Pathology and Therapeutics, Faculty of Medicine, University of Barcelona, L’Hospitalet del Llobregat, Barcelona, Spain

    Soledad Alcántara

  5. IDIBELL, L’Hospitalet del Llobregat, Barcelona, Spain

    José C. Perales

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  1. Jana Semakova
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  2. Petra Hyroššová
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  3. Andrés Méndez-Lucas
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  6. Shawn Burgess
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  7. Soledad Alcántara
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  8. José C. Perales
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Corresponding author

Correspondence to José C. Perales.

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Conflict of interest

The authors declare that they have no conflict of interest.

Funding

This work was supported by a grant from the Ministerio de Economia y Competitividad and by FEDER (BFU2012-37177 and BFU2015-66030-R) awarded to J.C.P. J.S., A.M.L., and P.H. have received fellowships from Ministerio de Educación y Ciencia or Ministerio de Economia y Competitividad.

Electronic supplementary material

Supplementary Figure 1

Brain histology (H&E). Cerebral cortex of Control P2 sibling (a), PEPCK-C KO Stage I (b) and Stage III (c). Hippocampus of Control P2 sibling (d), PEPCK-C KO in Stage I (e) and Stage III (f). Arrows indicate pyknotic nuclei. (DOCX 219 kb)

Supplementary Figure 2

Histology of ocular bulbs and retina (H&E) in Control P0.5 sibling (a) and Stage I PEPCK-C KO pup (b). No difference was observed between genotypes. (DOCX 68 kb)

Supplementary Figure 3

Stage III PEPCK-C histology (H&E). Renal cortex (a), pancreatic islet (b1), pancreatic acini (b2), urinary bladder (c), ureter (d), testis (e), stomach (f), duodenum (g), thyroid gland (h), cartilage (i) and esophagus (j). No abnormality was observed. (DOCX 226 kb)

Supplementary Figure 4

As a control of transduction, AdGFP was injected intraperitoneally to P0.5 pups. GFP expression (green) and nuclear marker TO-PRO3 (blue) can be observed in overlapping transmission and confocal fluorescence micrographs. Lung (10×) ( a ), WAT (40×) ( b ), Cerebellum (10×) ( c ), Kidney cortex (10×) ( d ), Liver (40×) ( e ), Pancreas (10×) ( f ), Spleen (10×) ( g ), Small intestine (10×) ( h ). (DOCX 7125 kb)

Supplementary Figure 5

Histology of hypothalamus of AdPck1 + KO and AdPck1 + Control animals, P8.5. Coronal sections of basal parts of prepeduncular hypothalamus, nuclear staining YOYO-1 in green, GFAP in red. GFAP: Glial fibrillary acidic protein. (DOCX 463 kb)

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Semakova, J., Hyroššová, P., Méndez-Lucas, A. et al. PEPCK-C reexpression in the liver counters neonatal hypoglycemia in Pck1 del/del mice, unmasking role in non-gluconeogenic tissues. J Physiol Biochem 73, 89–98 (2017). https://doi.org/10.1007/s13105-016-0528-y

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  • DOI: https://doi.org/10.1007/s13105-016-0528-y

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