Isomers of conjugated linoleic acid induce insulin resistance through a mechanism involving activation of protein kinase Cε in liver cells

Conjugated linoleic acid (CLA) constitutes a group of isomers derived from linoleic acid. Diverse studies have suggested that these unsaturated fatty acids have beneficial effects on human health. However, it has also been reported that their consumption can generate alterations in hepatic tissue. T...

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Published in:Cellular signalling 2019-01, Vol.53, p.281-293
Main Authors: Roura-Guiberna, Adriana, Hernandez-Aranda, Judith, Ramirez-Flores, Carlos Jorge, Mondragon-Flores, Ricardo, Garibay-Nieto, Nayely, Queipo-Garcia, Gloria, Laresgoiti-Servitje, Estibalitz, Soh, Jae-Won, Olivares-Reyes, Jesus Alberto
Format: Article
Language:English
Subjects:
Akt
Animals
Cell Line
Conjugated Linoleic Acid
Enzyme Activation
Insulin
Insulin - metabolism
Insulin Resistance
IRS
Isomerism
Linoleic Acids, Conjugated - metabolism
Liver - cytology
Liver - metabolism
Phosphorylation
Protein Kinase C-epsilon - metabolism
Protein Kinase Cε
Proto-Oncogene Proteins c-akt - metabolism
Rats
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Summary:Conjugated linoleic acid (CLA) constitutes a group of isomers derived from linoleic acid. Diverse studies have suggested that these unsaturated fatty acids have beneficial effects on human health. However, it has also been reported that their consumption can generate alterations in hepatic tissue. Thus, in the present study, we evaluated the effect of two of the major isomers of CLA, cis-9, trans-11-CLA and trans-10, cis-12-CLA, in the regulation of insulin signaling in a hepatic cell model, clone 9 (C9). We found that the two isomers decrease insulin-stimulated phosphorylation of the main proteins involved in insulin signaling, such as Akt at Ser473 and Thr308, the insulin receptor at Tyr1158, IRS-1 at Tyr632, and GSK-3 at Ser9/21. Protein expression, however, was unaffected. Interestingly, both isomers of CLA promoted phosphorylation and activation of PKCε. Inhibition of PKCε activity by a dominant-negative form or knockdown of endogenous PKCε prevented the adverse effects of CLA isomers on insulin-induced Akt phosphorylation. Additionally, we also found that both isomers of CLA increase phosphorylation of IRS-1 at Ser612, a mechanism that probably underlies the inhibition of IRS-1 signaling by PKCε. Using confocal microscopy, we found that both isomers of CLA induced lipid accumulation in C9 cells with the presence of spherical cytosolic vesicles, suggesting their identity as neutral lipid droplets. These findings indicate that cis-9, trans-11-CLA and trans-10, cis-12-CLA isomers could have a significant role in the development of insulin resistance in hepatic C9 cells through IRS-1 serine phosphorylation, PKCε activation, and hepatic lipid accumulation. [Display omitted] •cis-9, trans-11-CLA and trans-10, cis-12-CLA induce insulin resistance in hepatic cells•CLA isomers impair insulin-induced Akt phosphorylation through activation of PKCε•Once PKCε is activated by both CLA isomers, it promotes IRS-1 Ser612 phosphorylation•CLA isomers promote lipid deposition in hepatic C9 cells
ISSN:0898-6568
1873-3913
DOI:10.1016/j.cellsig.2018.10.013