Oxidized LDL impair adipocyte response to insulin by activating serine/threonine kinases

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 (240%) through reduced glucose transporter 4 (GLUT4) recruitment to the plasma membrane (270%), 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 kB-kinase b (IKKb) and the c-Jun NH 2 -terminal kinase ( JNK). Moreover, the activation of IKKb positively regulated the nuclear content of nuclear factor kB (NF-kB), by inactivating the inhibitor of NF-kB (IkBa). The activated NF-kB further impaired per se GLUT4 functionality. Specific inhibitors of IKKb, JNK, and NF-kB 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, B., R. Varì, M. DʼArchivio, C. Santangelo, C. Filesi, C. Giovannini, and R. Masella. Oxidized LDL impair adipocyte response to insulin by activating serine/threonine kinases. J. Lipid Res. 2009. 50: 832-845.

Lipokines and oxysterols: Novel adipose-derived lipid hormones linking adipose dysfunction and insulin resistance

“…Moreover, oxLDL and 7κ-C were also reported to impair (pre) adipocyte differentiation and induce IR in mature adipocytes [104,117,118]. On the other hand, as previously mentioned, oxysterols can also behave as antiadipogenic signals by diverting pluripotent mesenchymal cells′ fate away from adipogenic and in favor of the osteogenic lineage through transactivation of Wntmediated signaling pathway [90,104,119].…”

Association of a polymorphism in the 3' untranslated region of the <i>OLR1</i> gene with milk fat and protein in dairy cows

“…Using murine 3T3-L1 adipocytes, Scazzocchio et al (2009) showed that Ox-LDL can cause the impairment of insulin signalling likely because of insulin receptor substrate-1 degradation through enhanced Ser 307 phosphorylation. On the other hand, there is increasing evidence that Ox-LDL induces beta cell dysfunction and reduction of insulin production (Maziere et al 2004, Abderrahmani et al 2007, Favre et al 2011.…”

Oxidized LDL: Diversity, Patterns of Recognition, and Pathophysiology

“…Multiple studies have demonstrated that there is a clear connection between oxidative stress and development of type 2 diabetes mellitus (T2DM) that is related to insulin resistance. First, several reports showed increased plasma OxLDL levels in the metabolic syndrome as well as in T2DM and obesity (248). It is also known that hyperglycemia induces nonenzymatic oxidation of a variety of lipids and proteins.…”

“…in this process is OxLDL-induced impairment of glucose transporter 4 (GLUT4) (248). This transporter is stored in intracellular vesicles in insulin-sensitive cells like adipocytes and myocytes and translocates to the plasma membrane upon stimulation by insulin.…”