2024-03-29T12:14:29Zhttp://digital.csic.es/dspace-oai/requestoai:digital.csic.es:10261/1763492019-02-20T01:57:17Zcom_10261_105com_10261_1col_10261_358
2019-02-19T08:43:04Z
urn:hdl:10261/176349
VLDL and apolipoprotein CIII induce ER stress and inflammation and attenuate insulin signalling via Toll-like receptor 2 in mouse skeletal muscle cells
Botteri, Gaia
Montori, Marta
Gumà, Anna
Pizarro, Javier
Cedó, Lídia
Escolà-Gil, Joan Carles
Li, Diana
Barroso, Emma
Kohan, Alison B.
Vázquez-Carrera, Manuel
Ministerio de Economía y Competitividad (España)
Generalitat de Catalunya
National Institutes of Health (US)
Department of Agriculture (US)
National Institute of Food and Agriculture (US)
Instituto de Salud Carlos III
European Commission
Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (España)
AMPK
apoCIII
ERK1/2
TLR2
VLDL
[Aim/hypothesis] Here, our aim was to examine whether VLDL and apolipoprotein (apo) CIII induce endoplasmic reticulum (ER) stress, inflammation and insulin resistance in skeletal muscle.
[Methods] Studies were conducted in mouse C2C12 myotubes, isolated skeletal muscle and skeletal muscle from transgenic mice overexpressing apoCIII.
[Results] C2C12 myotubes exposed to VLDL showed increased levels of ER stress and inflammatory markers whereas peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) and AMP-activated protein kinase (AMPK) levels were reduced and the insulin signalling pathway was attenuated. The effects of VLDL were also observed in isolated skeletal muscle incubated with VLDL. The changes caused by VLDL were dependent on extracellular signal-regulated kinase (ERK) 1/2 since they were prevented by the ERK1/2 inhibitor U0126 or by knockdown of this kinase by siRNA transfection. ApoCIII mimicked the effects of VLDL and its effects were also blocked by ERK1/2 inhibition, suggesting that this apolipoprotein was responsible for the effects of VLDL. Skeletal muscle from transgenic mice overexpressing apoCIII showed increased levels of some ER stress and inflammatory markers and increased phosphorylated ERK1/2 levels, whereas PGC-1α levels were reduced, confirming apoCIII effects in vivo. Finally, incubation of myotubes with a neutralising antibody against Toll-like receptor 2 abolished the effects of apoCIII on ER stress, inflammation and insulin resistance, indicating that the effects of apoCIII were mediated by this receptor.
[Conclusions/interpretation] These results imply that elevated VLDL in diabetic states can contribute to the exacerbation of insulin resistance by activating ERK1/2 through Toll-like receptor 2.
2019-02-19T08:43:04Z
2019-02-19T08:43:04Z
2017-11
artículo
Diabetologia 60(11): 2262–2273 (2017)
0012-186X
10.1007/s00125-017-4401-5
http://hdl.handle.net/10261/176349
1432-0428
http://dx.doi.org/10.13039/501100000780
http://dx.doi.org/10.13039/501100004587
http://dx.doi.org/10.13039/100000002
http://dx.doi.org/10.13039/100005825
http://dx.doi.org/10.13039/501100002809
http://dx.doi.org/10.13039/501100003329
http://dx.doi.org/10.13039/100000199
eng
https://doi.org/10.1007/s00125-017-4401-5
Sí
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2015-64146-R
closedAccess
Springer