We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
The Role of Caveolin-Enriched Microdomains in Ceramide-Mediated Insulin Resistance.
- Authors
Hajduch, Eric; Turban, Sophie; Le Lay, Soazig; Dugail, Isabelle; Hundal, Harinder S.
- Abstract
An increase in intracellular ceramide has been shown to disrupt insulin signalling in both skeletal muscle and fat cells by targeting the insulin-induced activation of protein kinase B (PKB). We have shown that this inhibition involves increased association and phosphorylation of PKB by protein kinase CΖ (PKCΖ), but investigate here the possibility that ceramida may sequester these proteins in caveolin-enriched microdomains (CEM) where PKB may be held in a repressed state. CEM are enriched in cholesterol and sphingolipids and we found that treatment of cultured adipocytes and muscle cells with ceramide induced translocation of PKCΖ and PKB to CEM. Disrupting CEM in 3T3L1 adipocytas, human adipocytes and L6 muscle cells using methyl-beta-cyclodextrin, a cholesterol depleting agent ameliorated the inhibitory effect of ceramide on PKB activation by reducing PKCΖ association with PKB. We demonstrated the importance of caveolae themselves in this mechanism using adipocytes isolated from mice deficient in caveolin-1. Adipocytes lacking caveolae, showed a reduced capacity for PKCΖ to physically associate with and inhibit PKB in response to ceramida. As a consequence, the ability of ceramide to suppress the insulin-induced phosphorylation of PKB was also significantly diminished. Based on the view that caveolae are intramembrane sites that favour insulin action, we were also interested to determine how other key players of the insulin signalling pathway, known to be present in caveolae, behaved in response to ceramide. We showed that abundance of 3-phosphoinositide-dependent protein kinase 1 (PDK1), a member of the serine/threonine kinase family that is involved in PKB activation, was reduced in caveolae after ceramide treatment. In contrast, the content of PTEN, an important lipid phosphatase which negatively regulates the insulin signalling pathway was significantly elevated in CEM in response to increased ceramide availability. Collectively, our findings indicate that ceramide induces insulin resistance by inhibiting and/or modifying the abundance of molecules that participate in proximal insulin signalling within CEM.
- Publication
Diabetes, 2007, Vol 56, pA35
- ISSN
0012-1797
- Publication type
Academic Journal