Oxidized low-density lipoproteins impair adipocyte response to insulin by activating serine/threonine kinases

Beatrice Scazzocchio, Rosaria Varì, Massimo D'Archivio, Carmela Santangelo, Carmelina Filesi, Claudio Giovannini, and Roberta Masella

Veterinary Public Health and Food Safety, Istituto Superiore di Sanità, Roma

Corresponding Author: masellar{at}iss.it

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 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 B-kinase $beta$ (IKK $beta$ ) and the c-Jun NH2-terminal kinase (JNK). Moreover, the activation of IKK $beta$ positively regulated the nuclear content of NF-B, by inactivating the inhibitor of NF-B (IBa). The activated NF-B further impaired per se GLUT4 functionality. Specific inhibitors of IKK $beta$ , JNK and NF-B 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. This suggests that oxLDL might participate in the development of insulin resistance

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