PEPCK-C reexpression in the liver counters neonatal hypoglycemia in Pck1 del/del mice, unmasking role in non-gluconeogen
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ORIGINAL ARTICLE
PEPCK-C reexpression in the liver counters neonatal hypoglycemia in Pck1del/del mice, unmasking role in non-gluconeogenic tissues Jana Semakova 1 & Petra Hyroššová 1 & Andrés Méndez-Lucas 1 & Ernest Cutz 2 & Jordi Bermudez 1 & Shawn Burgess 3 & Soledad Alcántara 4 & José C. Perales 1,5
Received: 31 March 2016 / Accepted: 5 October 2016 # University of Navarra 2016
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-Cexpressing 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
Electronic supplementary material The online version of this article (doi:10.1007/s13105-016-0528-y) contains supplementary material, which is available to authorized users. * José C. Perales [email protected] 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
IDIBELL, L’Hospitalet del Llobregat, Barcelona, Spain
assessment of survivors also suggest a possible role for PEPCK-C in lung maturation and muscle metabolism. Keywords PEPCK . Gluconeogenesis . Liver . Neonatal hypoglycemia . KO . Hepatic lipidosis
Introduction Phosphoenolpyruvate carboxykinase (PEPCK, EC 4.1.1.32) catalyzes a GTP-dependent decarboxylation of oxaloacetate to phosphoenolpyruvate as the first committed step in gluconeogenesis/glyceroneogenesis in liver, kidney, and adipose tissue [21]. Two isoforms have been described: cytosolic (PEPCK-C, encoded by nuclear gene Pck1) and mitochondrial (PEPCK-M, encoded by nuclear gene Pck2) PEPCK, with completely different regulation and expression pattern [1, 13, 14]. Cytosolic PEPCK is prevalent in the mouse liver (up to 98–99 %) [13], an animal model commonly utilized for metabolic studies. The activity of PEPCK is proportional to its protein level, as there are no known allosteric modifiers. Transcription of Pck1 (PEPCK-C) is enhanced by glucagon, adrenaline, glucocorticoids, and thyroid hormone and inhibited by insulin [19]. Over the
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