VLDL and apolipoprotein CIII induce ER stress and inflammation and attenuate insulin signalling via Toll-like receptor 2 in mouse skeletal muscle cells
Por:
Botteri, G, Montori, M, Guma, A, Pizarro, J, Cedo, L, Escola-Gil, JC, Li, D, Barroso, E, Palomer, X, Kohan, AB, Vazquez-Carrera, M
Publicada:
1 nov 2017
Resumen:
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 gamma co-activator 1 alpha (PGC-1 alpha) 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-1a 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.
Filiaciones:
Botteri, G:
Univ Barcelona, IBUB, Fac Pharm & Food Sci, Pharmacol Unit,Dept Pharmacol Toxicol & Therapeut, Diagonal 643, E-08028 Barcelona, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Diabet & Enfermedad Metab A, Barcelona, Spain
IR SJD, Barcelona, Spain
Montori, M:
Univ Barcelona, IBUB, Fac Pharm & Food Sci, Pharmacol Unit,Dept Pharmacol Toxicol & Therapeut, Diagonal 643, E-08028 Barcelona, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Diabet & Enfermedad Metab A, Barcelona, Spain
IR SJD, Barcelona, Spain
Guma, A:
Inst Salud Carlos III, Ctr Invest Biomed Red Diabet & Enfermedad Metab A, Barcelona, Spain
Univ Barcelona, Dept Biochem & Mol Biol, Barcelona, Spain
Univ Barcelona, IBUB, Barcelona, Spain
Pizarro, J:
Univ Barcelona, IBUB, Fac Pharm & Food Sci, Pharmacol Unit,Dept Pharmacol Toxicol & Therapeut, Diagonal 643, E-08028 Barcelona, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Diabet & Enfermedad Metab A, Barcelona, Spain
IR SJD, Barcelona, Spain
Cedo, L:
Inst Salud Carlos III, Ctr Invest Biomed Red Diabet & Enfermedad Metab A, Barcelona, Spain
Inst Invest Biomed IIB St Pau, Barcelona, Spain
Escola-Gil, JC:
Inst Salud Carlos III, Ctr Invest Biomed Red Diabet & Enfermedad Metab A, Barcelona, Spain
Inst Invest Biomed IIB St Pau, Barcelona, Spain
Autonomous Univ Barcelona, Dept Biochem & Mol Biol, Barcelona, Spain
Li, D:
Univ Connecticut, Dept Nutr Sci, Storrs, CT USA
Barroso, E:
Univ Barcelona, IBUB, Fac Pharm & Food Sci, Pharmacol Unit,Dept Pharmacol Toxicol & Therapeut, Diagonal 643, E-08028 Barcelona, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Diabet & Enfermedad Metab A, Barcelona, Spain
IR SJD, Barcelona, Spain
Palomer, X:
Univ Barcelona, IBUB, Fac Pharm & Food Sci, Pharmacol Unit,Dept Pharmacol Toxicol & Therapeut, Diagonal 643, E-08028 Barcelona, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Diabet & Enfermedad Metab A, Barcelona, Spain
IR SJD, Barcelona, Spain
Kohan, AB:
Univ Connecticut, Dept Nutr Sci, Storrs, CT USA
Vazquez-Carrera, M:
Univ Barcelona, IBUB, Fac Pharm & Food Sci, Pharmacol Unit,Dept Pharmacol Toxicol & Therapeut, Diagonal 643, E-08028 Barcelona, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Diabet & Enfermedad Metab A, Barcelona, Spain
IR SJD, Barcelona, Spain
Green Accepted, Bronze
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