Oxidized LDL impair adipocyte response to insulin by activating serine/threonine kinases
AUTOR(ES)
Scazzocchio, Beatrice
FONTE
American Society for Biochemistry and Molecular Biology
RESUMO
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 Ser307phosphorylation. This process was largely mediated by the activation of the inhibitor of κB-kinase β (IKKβ) and the c-Jun NH2-terminal kinase (JNK). Moreover, the activation of IKKβ positively regulated the nuclear content of nuclear factor κB (NF-κB), by inactivating the inhibitor of NF-κB (IκBα). The activated NF-κB further impaired per se GLUT4 functionality. Specific inhibitors of IKKβ, JNK, and NF-κB 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.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2666169Documentos Relacionados
- STY, a tyrosine-phosphorylating enzyme with sequence homology to serine/threonine kinases.
- Pim serine/threonine kinases regulate the stability of Socs-1 protein
- Characterization of a Hank’s Type Serine/Threonine Kinase and Serine/Threonine Phosphoprotein Phosphatase in Pseudomonas aeruginosa
- Structural basis and prediction of substrate specificity in protein serine/threonine kinases
- Eukaryotic phytochromes: Light-regulated serine/threonine protein kinases with histidine kinase ancestry