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Pck1 gene silencing in the liver improves glycemia control, insulin sensitivity and dislipidemia in db/db mice

From the ¹Biophysics Unit, Department of Physiological Sciences II, IDIBELL-University of Barcelona, Feixa Llarga s/n, 08907, L'Hospitalet del Llobregat, Spain
²Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, Barcelona, Spain

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, together with 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. In spite of hepatic lipidosis, treatment resulted in improved insulin signaling in the liver, muscle and adipose. O₂ consumption measurements in isolated hepatocytes demonstrated unaltered mitochondrial function and a consequent increased cellular energy charge. Key regulatory factors (FOXO1, HNF4 and PGC-1) and enzymes (G6Pase) implicated in gluconeogenesis were down-regulated after treatment. Finally, the levels of Sirt1, a redox-state sensor that modulates gluconeogenesis through PGC1-, 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.

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