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Oxidized LDL impair adipocyte response to insulin by activating serine/threonine kinases.
J Lipid Res. 2009 May; 50(5):832-45.JL

Abstract

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.

Authors+Show Affiliations

Department of Veterinary Public Health and Food Safety, Istituto Superiore di Sanità, Rome, Italy.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

19136667

Citation

Scazzocchio, Beatrice, et al. "Oxidized LDL Impair Adipocyte Response to Insulin By Activating Serine/threonine Kinases." Journal of Lipid Research, vol. 50, no. 5, 2009, pp. 832-45.
Scazzocchio B, Varì R, D'Archivio M, et al. Oxidized LDL impair adipocyte response to insulin by activating serine/threonine kinases. J Lipid Res. 2009;50(5):832-45.
Scazzocchio, B., Varì, R., D'Archivio, M., Santangelo, C., Filesi, C., Giovannini, C., & Masella, R. (2009). Oxidized LDL impair adipocyte response to insulin by activating serine/threonine kinases. Journal of Lipid Research, 50(5), 832-45. https://doi.org/10.1194/jlr.M800402-JLR200
Scazzocchio B, et al. Oxidized LDL Impair Adipocyte Response to Insulin By Activating Serine/threonine Kinases. J Lipid Res. 2009;50(5):832-45. PubMed PMID: 19136667.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Oxidized LDL impair adipocyte response to insulin by activating serine/threonine kinases. AU - Scazzocchio,Beatrice, AU - Varì,Rosaria, AU - D'Archivio,Massimo, AU - Santangelo,Carmela, AU - Filesi,Carmelina, AU - Giovannini,Claudio, AU - Masella,Roberta, Y1 - 2009/01/09/ PY - 2009/1/13/entrez PY - 2009/1/13/pubmed PY - 2009/7/8/medline SP - 832 EP - 45 JF - Journal of lipid research JO - J. Lipid Res. VL - 50 IS - 5 N2 - 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. SN - 0022-2275 UR - https://www.unboundmedicine.com/medline/citation/19136667/Oxidized_LDL_impair_adipocyte_response_to_insulin_by_activating_serine/threonine_kinases_ L2 - http://www.jlr.org/cgi/pmidlookup?view=long&pmid=19136667 DB - PRIME DP - Unbound Medicine ER -