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Suppression of 5 '-Nucleotidase Enzymes Promotes AMP-activated Protein Kinase (AMPK) Phosphorylation and Metabolism in Human and Mouse Skeletal Muscle
Karolinska Institutet, Stockholm, Sweden.
Karolinska Institutet, Stockholm, Sweden.
Karolinska Institutet, Stockholm, Sweden.
Karolinska Institutet, Stockholm, Sweden.ORCID iD: 0000-0002-6339-6271
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2011 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 286, no 40, 34567-34574 p.Article in journal (Refereed) Published
Abstract [en]

The 5'-nucleotidase (NT5) family of enzyme dephosphorylates non-cyclic nucleoside monophosphates to produce nucleosides and inorganic phosphates. We hypothesized that gene silencing of NT5 enzymes to increase the intracellular availability of AMP would increase AMP-activated protein kinase (AMPK) activity and metabolism. We determined the role of cytosolic NT5 in metabolic responses linked to the development of insulin resistance in obesity and type 2 diabetes. Using siRNA to silence NT5C2 expression in cultured human myotubes, we observed a 2-fold increase in the AMP/ATP ratio, a 2.4-fold increase in AMPK phosphorylation (Thr(172)), and a 2.8-fold increase in acetyl-CoA carboxylase phosphorylation (Ser(79)) (p<0.05). siRNA silencing of NT5C2 expression increased palmitate oxidation by 2-fold in the absence and by 8-fold in the presence of 5-aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside. This was paralleled by an increase in glucose transport and a decrease in glucose oxidation, incorporation into glycogen, and lactate release from NT5C2-depleted myotubes. Gene silencing of NT5C1A by shRNA injection and electroporation in mouse tibialis anterior muscle reduced protein content (60%; p<0.05) and increased phosphorylation of AMPK (60%; p<0.05) and acetyl-CoA carboxylase (50%; p<0.05) and glucose uptake (20%; p<0.05). Endogenous expression of NT5C enzymes inhibited basal lipid oxidation and glucose transport in skeletal muscle. Reduction of 5'-nucleotidase expression or activity may promote metabolic flexibility in type 2 diabetes.

Place, publisher, year, edition, pages
2011. Vol. 286, no 40, 34567-34574 p.
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Physiology
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URN: urn:nbn:se:his:diva-13784DOI: 10.1074/jbc.M111.268292ISI: 000295406300011PubMedID: 21873433Scopus ID: 2-s2.0-80053411075OAI: oai:DiVA.org:his-13784DiVA: diva2:1112173
Available from: 2017-06-20 Created: 2017-06-20 Last updated: 2017-11-27Bibliographically approved

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Szekeres, FerencChibalin, Alexander V.Krook, AnnaZierath, Juleen R.

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