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Diabetologia. 2017 Nov;60(11):2262-2273. doi: 10.1007/s00125-017-4401-5. Epub 2017 Aug 23.

VLDL and apolipoprotein CIII induce ER stress and inflammation and attenuate insulin signalling via Toll-like receptor 2 in mouse skeletal muscle cells.

Author information

1
Pharmacology Unit, Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institut de Biomedicina de la Universidad de Barcelona (IBUB), University of Barcelona, Diagonal 643, E-08028, Barcelona, Spain.
2
Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Barcelona, Spain.
3
Institut de Recerca Sant Joan de Déu (IR-SJD), Esplugues de Llobregat, Barcelona, Spain.
4
Department of Biochemistry and Molecular Biology and IBUB, University of Barcelona, Barcelona, Spain.
5
Institut d'Investigacions Biomèdiques (IIB) Sant Pau, Barcelona, Spain.
6
Department of Biochemistry and Molecular Biology, Autonomous University of Barcelona, Barcelona, Spain.
7
Department of Nutritional Sciences, University of Connecticut, Storrs, CT, USA.
8
Pharmacology Unit, Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institut de Biomedicina de la Universidad de Barcelona (IBUB), University of Barcelona, Diagonal 643, E-08028, Barcelona, Spain. mvazquezcarrera@ub.edu.
9
Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Barcelona, Spain. mvazquezcarrera@ub.edu.
10
Institut de Recerca Sant Joan de Déu (IR-SJD), Esplugues de Llobregat, Barcelona, Spain. mvazquezcarrera@ub.edu.

Abstract

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.

KEYWORDS:

AMPK; ERK1/2; TLR2; VLDL; apoCIII

PMID:
28835988
PMCID:
PMC6078195
DOI:
10.1007/s00125-017-4401-5
[Indexed for MEDLINE]
Free PMC Article

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