Membrane Organization and Regulation of Cellular Cholesterol Homeostasis
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An excess of intracellular free cholesterol (Chol) is cytotoxic, and its homeostasis is crucial for cell viability. Apolipoprotein A-I (apoA-I) is a highly efficient Chol acceptor because it activates complex cellular pathways that tend to mobilize and export Chol from cellular depots. We hypothesize that membrane composition and/or organization is strongly involved in Chol homeostasis. To test this hypothesis, we constructed a cell line overexpressing stearoyl coenzyme A (CoA) desaturase (SCD cells), which modifies plasma membrane (PM) composition by the enrichment of monounsaturated fatty acids, and determined this effect on membrane properties, cell viability, and Chol homeostasis. PM in SCD cells has a higher ratio of phospholipids to sphingomyelin and is slightly enriched in Chol. These cells showed an increase in the ratio of cholesteryl esters to free Chol; they were more resistant to Chol toxicity, and they exported more caveolin than control cells. The data suggest that cell functionality is preserved by regulating membrane fluidity and Chol exportation and storage.
KeywordsStearoyl CoA desaturase Human apolipoprotein A-I Membrane heterogeneity Cholesterol transport Chinese hamster ovary cells Intracellular cholesterol storage Caveolin Cytotoxicity
The work presented here was supported by the Agencia Nacional de Promoción Científica y Tecnológica, Argentina, grants 14443 to OJR and 26228 to HAG, Consejo de Investigaciones Científicas y Técnicas (PIP 112-200801-00953 to HAG), and the Australian Fluorescence Foundation R108 and International Cooperation (CONICET) to MAT. We thank L. Hernandez for her expertise and technical support with apoA-I purification and figure preparation. OJR, HAG, MCG, and MAT are members of the Carrera del Investigador Científico (CONICET), Argentina. SS acknowledges the National Institutes of Health (grant PHS 5 P41 RR-03155, US).
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