FABP4 inhibitor BMS309403 decreases saturated-fatty-acid-induced endoplasmic reticulum stress-associated inflammation in skeletal muscle by reducing p38 MAPK activation.
Biochim Biophys Acta Mol Cell Biol Lipids
; 1863(6): 604-613, 2018 Jun.
Article
en En
| MEDLINE
| ID: mdl-29550588
ABSTRACT
AIMS:
Fatty acid binding protein 4 (FABP4) inhibitors have been proposed as potential therapeutic approaches against insulin resistance-related inflammation and type 2 diabetes mellitus. However, the underlying molecular mechanisms by which these molecules drive these effects in skeletal muscle remain unknown. Here, we assessed whether the FABP4 inhibitor BMS309403 prevented lipid-induced endoplasmic reticulum (ER) stress-associated inflammation in skeletal muscle. MATERIALS ANDMETHODS:
The BMS309403 treatment was assessed both in the skeletal muscle of high-fat diet (HFD)-fed mice and in palmitate-stimulated C2C12 myotubes.RESULTS:
HFD feeding promoted insulin resistance, which is characterized by increased plasma levels of glucose, insulin, non-esterified fatty acids, triglycerides, resistin, and leptin and reduced plasma levels of adiponectin compared with control mice fed a standard diet. Additionally, insulin-resistant animals showed increased FABP4 plasma levels. In line with this evidence, recombinant FABP4 attenuated the insulin-induced AKT phosphorylation in C2C12 myotubes. Treatment with BMS309403 reduced lipid-induced ER stress and inflammation in both mouse skeletal muscle and C2C12 myotubes. The effects of the FABP4 inhibitor reducing lipid-induced ER stress-associated inflammation were related to the reduction of fatty acid-induced intramyocellular lipid deposits, ROS and nuclear factor-kappaB (NF-κB) nuclear translocation. Accordingly, BMS309403 reduced lipid-induced p38 MAPK phosphorylation, which is upstream of NF-κB activation.CONCLUSION:
Overall, these findings indicate that BMS309403 reduces fatty acid-induced ER stress-associated inflammation in skeletal muscle by reducing p38 MAPK activation.Palabras clave
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Pirazoles
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Compuestos de Bifenilo
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Músculo Esquelético
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Sistema de Señalización de MAP Quinasas
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Proteínas Quinasas p38 Activadas por Mitógenos
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Proteínas de Unión a Ácidos Grasos
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Ácidos Grasos
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Estrés del Retículo Endoplásmico
Tipo de estudio:
Risk_factors_studies
Idioma:
En
Revista:
Biochim Biophys Acta Mol Cell Biol Lipids
Año:
2018
Tipo del documento:
Article