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Journal of Lipid Research, Vol. 50, 832-845, May 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

Oxidized LDL 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 Masella¹

Department of Veterinary Public Health and Food Safety, Istituto Superiore di Sanità, Rome, Italy

Published, JLR Papers in Press, January 9, 2009.

¹ To whom correspondence should be addressed. e-mail: 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 (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 B-kinase β (IKKβ) and the c-Jun NH₂-terminal kinase (JNK). Moreover, the activation of IKKβ positively regulated the nuclear content of nuclear factor B (NF-B), by inactivating the inhibitor of NF-B (IB). The activated NF-B further impaired per se GLUT4 functionality. Specific inhibitors of IKKβ, 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 (PM). This suggests that oxLDL might participate in the development of insulin resistance.

Supplementary key words insulin resistance • GLUT4 • IRS-1 • IKKβ • NF-B

Abbreviations: 15d-PGJ₂, 15-deoxy-^12,14-prostaglandin J₂; CTR, control; GLUT4, glucose transporter 4; IBs, inhibitory B proteins; IKKβ, inhibitor of kappa B kinase β; IR, insulin receptor; IRS, insulin receptor substrate; JNK, c-Jun NH₂-terminal kinase; NF-B, nuclear factor B; oxLDL, oxidized LDL; PM, plasma membranes; 2-DG, 2-deoxyglucose; ROS, reactive oxygen species

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