A role for protein phosphatase 2A-like activity, but not atypical protein kinase Czeta, in the inhibition of protein kinase B/Akt and glycogen synthesis by palmitate
- PMID: 11574400
- DOI: 10.2337/diabetes.50.10.2210
A role for protein phosphatase 2A-like activity, but not atypical protein kinase Czeta, in the inhibition of protein kinase B/Akt and glycogen synthesis by palmitate
Abstract
We have shown previously that palmitate treatment of C2C12 skeletal muscle myotubes causes inhibition of the protein kinase B (PKB) pathway and hence reduces insulin-stimulated glycogen synthesis through the elevation of intracellular ceramide levels. Ceramide is known to activate both atypical protein kinase C (aPKC) zeta and protein phosphatase (PP) 2A, and each of these effectors has been reported to inhibit PKB. In the present study, palmitate pretreatment was found to elevate PP2A-like activity in myotubes and to prevent its inhibition by insulin. Incubation with the phosphatase inhibitor okadaic acid before insulin stimulation protected against the effect of the fatty acid on PKB phosphorylation. Palmitate was unable to inhibit PKB activity and glycogen synthesis in cells overexpressing the activated PKB mutant (T308D,S473D)-PKBalpha, which is unaffected by phosphatase. In contrast, PKB activity and glycogen synthesis were still inhibited by palmitate in cells overexpressing a membrane-targeted and, hence, activated PKB mutant that retains sensitivity to phosphatase. Although aPKC activity was also increased in palmitate-treated cells, overexpression of wild-type or kinase-dead aPKCzeta did not alter the inhibitory effects of the lipid on either stimulation of PKB or glycogen synthesis by insulin. We conclude that palmitate disrupts insulin signaling in C2C12 myotubes by promoting PP2A-like activity and, therefore, the dephosphorylation of PKB, which in turn reduces the stimulation of glycogen synthesis.
Similar articles
-
Ceramide generation is sufficient to account for the inhibition of the insulin-stimulated PKB pathway in C2C12 skeletal muscle cells pretreated with palmitate.J Biol Chem. 1999 Aug 20;274(34):24202-10. doi: 10.1074/jbc.274.34.24202. J Biol Chem. 1999. PMID: 10446195
-
Characterizing the effects of saturated fatty acids on insulin signaling and ceramide and diacylglycerol accumulation in 3T3-L1 adipocytes and C2C12 myotubes.Arch Biochem Biophys. 2003 Nov 15;419(2):101-9. doi: 10.1016/j.abb.2003.08.020. Arch Biochem Biophys. 2003. PMID: 14592453
-
Characterising the inhibitory actions of ceramide upon insulin signaling in different skeletal muscle cell models: a mechanistic insight.PLoS One. 2014 Jul 24;9(7):e101865. doi: 10.1371/journal.pone.0101865. eCollection 2014. PLoS One. 2014. PMID: 25058613 Free PMC article.
-
Protein phosphatase-1 and insulin action.Mol Cell Biochem. 1998 May;182(1-2):49-58. Mol Cell Biochem. 1998. PMID: 9609113 Review.
-
Protein kinase C and lipid-induced insulin resistance in skeletal muscle.Ann N Y Acad Sci. 2002 Jun;967:146-57. doi: 10.1111/j.1749-6632.2002.tb04272.x. Ann N Y Acad Sci. 2002. PMID: 12079844 Review.
Cited by
-
Palmitic Acid Induces Posttranslational Modifications of Tau Protein in Alzheimer's Disease-Related Epitopes and Increases Intraneuronal Tau Levels.Mol Neurobiol. 2024 Aug;61(8):5129-5141. doi: 10.1007/s12035-023-03886-8. Epub 2024 Jan 3. Mol Neurobiol. 2024. PMID: 38167971 Free PMC article.
-
Protein Phosphatase 2A as a Therapeutic Target in Pulmonary Diseases.Medicina (Kaunas). 2023 Aug 26;59(9):1552. doi: 10.3390/medicina59091552. Medicina (Kaunas). 2023. PMID: 37763671 Free PMC article. Review.
-
Hepatic IRF3 fuels dysglycemia in obesity through direct regulation of Ppp2r1b.Sci Transl Med. 2022 Mar 23;14(637):eabh3831. doi: 10.1126/scitranslmed.abh3831. Epub 2022 Mar 23. Sci Transl Med. 2022. PMID: 35320000 Free PMC article.
-
The aetiology and molecular landscape of insulin resistance.Nat Rev Mol Cell Biol. 2021 Nov;22(11):751-771. doi: 10.1038/s41580-021-00390-6. Epub 2021 Jul 20. Nat Rev Mol Cell Biol. 2021. PMID: 34285405 Review.
-
Roles of Ceramides in Non-Alcoholic Fatty Liver Disease.J Clin Med. 2021 Feb 16;10(4):792. doi: 10.3390/jcm10040792. J Clin Med. 2021. PMID: 33669443 Free PMC article. Review.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Miscellaneous