The DOI matches its Crossref record; 49 of the 49 references it cites were found in a registry or an index.
Intracellular ceramide synthesis and protein kinase Cζ activation play an essential role in palmitate-induced insulin resistance in rat L6 skeletal muscle cells
Open accessAbstract
Non-esterified fatty acids (NEFAs) have been implicated in the pathogenesis of skeletal muscle insulin resistance that may develop, in part, as a consequence of a direct inhibitory effect on early insulin signalling events. Here we report work investigating the mechanism by which palmitate (a saturated free fatty acid) inhibits insulin action in rat L6 myotubes. Palmitate suppressed the insulin-induced plasma membrane recruitment and phosphorylation of protein kinase B (PKB) and this was associated with a loss in insulin-stimulated glucose transport. The inhibition in PKB was not due to a loss in insulin receptor substrate (IRS)1 tyrosine phosphorylation, IRS-1/p85 (phosphoinositide 3-kinase) association or suppression in phosphatidyl 3,4,5 triphosphate synthesis, but was attributable to an elevated intracellular synthesis of ceramide (6-fold) from palmitate and a concomitant activation of protein kinase PKCζ (5-fold). Inhibitors of serine palmitoyl transferase suppressed the intracellular synthesis of ceramide from palmitate, prevented PKCζ activation, and antagonized the inhibition in PKB recruitment/phosphorylation and the loss in insulin-stimulated glucose transport elicited by the NEFA. Inhibiting the palmitate-induced activation of PKCζ with Ro 31.8220, also prevented the loss in the insulin-dependent phosphorylation of PKB caused by palmitate. These findings indicate that intracellular ceramide synthesis and PKCζ activation are important aspects of the mechanism by which palmitate desensitizes L6 muscle cells to insulin.
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“Lipid overload impairs oxidative capacity and increases the intracellular accumulation of FA-derived metabolites, such as long-chain acyl-CoA, diacylglycerol, ceramide, and triacylglycerol, in skeletal muscle (1, 30, 35, 37).”
From Mitochondrial Fission Contributes to Mitochondrial Dysfunction and Insulin Resistance in Skeletal Muscle (2012) · cites this paper as [35]
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“Increases in these lipid derivatives, particularly ceramides, can lead to the activation of PKC isoforms which lead to the phosphorylation of serine residues on insulin receptor substrate-1(IRS) and attenuating PKB activation [119,120].”
From Omega-3 Fatty Acids and Skeletal Muscle Health (2015) · cites this paper as [119]
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“The actions of these stimuli serve to not only further induce tissue expression and secretion of IL-6 and TNFα (via the NFκB pathway, [3, 4]), but impair control of numerous signalling pathways regulating skeletal muscle insulin signalling, glucose uptake, mitochondrial fuel oxidation and respiration that impact negatively upon skeletal muscle energy homeostasis [2, 5–7].”
From Proinflammatory NFkB signalling promotes mitochondrial dysfunction in skeletal muscle in response to cellular fuel overloading (2019) · cites this paper as [6]
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Metadata
- Authors
- POWELL, D. J., TURBAN, S., GRAY, A., HAJDUCH, E., & HUNDAL, H. S.
- Affiliations
- University of Dundee (GB)
- Division of Molecular Physiology, Faculty of Life Sciences, MSI/WTB Complex, University of Dundee, Dundee, DD1 5EH, Scotland
- Corresponding author
- TURBAN, Sophie
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 2004-08-24
- Volume
- 382
- Issue
- 2
- Pages
- 619-629
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- PMC
- PMC1133819
- OpenAlex
- W1967737207
- Cited by
- 267
- References
- 48
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 7 · 2023: 2 · 2022: 12 · 2021: 6 · 2020: 9 · 2019: 11 · 2018: 9 · 2017: 14 · 2016: 15 · 2015: 19 · 2014: 12 · 2013: 24 · 2012: 11
- FWCI
- 3.91
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Biochemical Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (submittedVersion)
- Funders
- Diabetes Research and Wellness Foundation
- Fondation pour la Recherche Médicale
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
- Keywords
- palmitate, insulin resistance, ceramide synthesis, protein kinase C zeta, skeletal muscle, L6 myotubes, free fatty acids, Akt, insulin signaling, glucose transport, serine palmitoyltransferase, Ro 31-8220, IRS-1, phosphatidylinositol 3,4,5-trisphosphate
- MeSH terms
- Protein Kinase C zeta, Animals, Cell Line, Ceramides, Enzyme Activation, Insulin Resistance, Palmitates, Protein Kinase C, Adipocytes, Muscle, Skeletal, Muscle Fibers, Skeletal, 3T3-L1 Cells, Intracellular Space, Mice, Rats
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