Oxidized LDL impair adipocyte response to insulin by activating serine/threonine kinases.
Oxidized LDL (oxLDL) increase in patients affected by type-2 diabetes, obesity, and metabolic syndrome. Likewise, insulin resistance, an impaired responsiveness of target tissues to insulin, is associated with those pathological conditions. To investigate a possible causal relationship between oxLDL and the onset of insulin resistance, we evaluated the response to insulin of 3T3-L1 adipocytes treated with oxLDL. We observed that oxLDL inhibited glucose uptake (-40%) through reduced glucose transporter 4 (GLUT4) recruitment to the plasma membrane (-70%), without affecting GLUT4 gene expression. These findings were associated to the impairment of insulin signaling. Specifically, in oxLDL-treated cells insulin receptor (IR) substrate-1 (IRS-1) was highly degraded likely because of the enhanced Ser(307)phosphorylation. This process was largely mediated by the activation of the inhibitor of kappaB-kinase beta (IKKbeta) and the c-Jun NH(2)-terminal kinase (JNK). Moreover, the activation of IKKbeta positively regulated the nuclear content of nuclear factor kappaB (NF-kappaB), by inactivating the inhibitor of NF-kappaB (IkappaBalpha). The activated NF-kappaB further impaired per se GLUT4 functionality. Specific inhibitors of IKKbeta, JNK, and NF-kappaB restored insulin sensitivity in adipocytes treated with oxLDL. These data provide the first evidence that oxLDL, by activating serine/threonine kinases, impaired adipocyte response to insulin affecting pathways involved in the recruitment of GLUT4 to plasma membranes (PM). This suggests that oxLDL might participate in the development of insulin resistance.
Scazzocchio
Beatrice
B
Department of Veterinary Public Health and Food Safety, Istituto Superiore di Sanità, Rome, Italy.
Varì
Rosaria
R
D'Archivio
Massimo
M
Santangelo
Carmela
C
Filesi
Carmelina
C
Giovannini
Claudio
C
Masella
Roberta
R
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000201:enzymology; D000818:Animals; D004789:Enzyme Activation; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*
D051275:Glucose Transporter Type 4; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D008077:Lipoproteins, LDL; D016328:NF-kappa B; C099252:oxidized low density lipoprotein; D017346:Protein Serine-Threonine Kinases; D051550:I-kappa B Kinase; D048031:JNK Mitogen-Activated Protein Kinases; D005947:Glucose