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Title: Pck1 gene silencing in the liver improves glycemia control, insulin sensitivity and dyslipidemia in db/db mice
Author: Gómez Valadés, Alicia G.
Méndez-Lucas, Andrés
Vidal Alabró, Anna
Blasco, Francesc
Chillón, Miguel
Bartrons Bach, Ramon
Bermúdez i Mas, Jordi
Perales Losa, Carlos
Keywords: Diabetis
Resistència a la insulina
Insulin resistance
Issue Date: Aug-2008
Publisher: American Diabetes Association
Abstract: Objective: cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C; encoded by Pck1) catalyzes the first committed step in gluconeogenesis. Extensive evidence demonstrates a direct correlation between PEPCK-C activity and glycemia control. Therefore, we aimed to evaluate the metabolic impact and their underlying mechanisms of knocking down hepatic PEPCK-C in a type 2 diabetic model. Research design and methods: PEPCK-C gene targeting was achieved using adenovirus-transduced RNAi. The study assessed several clinical symptoms of diabetes and insulin signaling in peripheral tissues, in addition to changes in gene expression, protein, and metabolites in the liver. Liver bioenergetics was also evaluated. Results: treatment resulted in reduced PEPCK-C mRNA and protein. After treatment, improved glycemia and insulinemia, lower triglyceride, and higher total and HDL cholesterol were measured. Unsterified fatty acid accumulation was observed in the liver, in the absence of de novo lipogenesis. Despite hepatic lipidosis, treatment resulted in improved insulin signaling in the liver, muscle, and adipose tissue. O(2) consumption measurements in isolated hepatocytes demonstrated unaltered mitochondrial function and a consequent increased cellular energy charge. Key regulatory factors (FOXO1, hepatocyte nuclear factor-4alpha, and peroxisome proliferator-activated receptor-gamma coactivator [PGC]-1alpha) and enzymes (G6Pase) implicated in gluconeogenesis were downregulated after treatment. Finally, the levels of Sirt1, a redox-state sensor that modulates gluconeogenesis through PGC-1alpha, were diminished. Conclusions: our observations indicate that silencing PEPCK-C has direct impact on glycemia control and energy metabolism and provides new insights into the potential significance of the enzyme as a therapeutic target for the treatment of diabetes.
Note: Reproducció del document publicat a:
It is part of: Diabetes, 2008, vol. 57, num. 8, p. 2199-2210
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ISSN: 0012-1797
Appears in Collections:Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
Articles publicats en revistes (Ciències Fisiològiques)

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