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Identification of key regulators of the caveolar-endocytic pathway from cell surface to lipid droplets : Physiological importance for intracellular storage of nutrients


Nutrients overload leads to adipocyte hypertrophy and excess of adipose tissue causing deleterious consequences known as the metabolic syndrome. During my post-doc, we showed that the fat cell surface and the lipid droplet can communicate through an ER-ind ependent endocytic caveolar pathway of critical importance in targeting cholesterol to lipid droplets. This caveolin-dependent route could therefore function more generally to supply lipids to adipocyte lipid droplets. In order to identify key regulators o f this pathway, we will design a screen assay based on microscopy imaging. We will use caveolin fused to the green fluorescent protein (GFP) and the lipid droplet marker adipophilin fused to the red fluorescent protein (RFP). In lipid-loading conditions, c aveolins associate with fat bodies, resulting in the co-localization of the two proteins and yellow colour (merge of green and red emitted fluorescence). By combining this assay with RNAinterference of kinases genes, we hope to identify knock-downs which r everse this phenotype by screening for distinct red and green fluorescence patterns. An important issue is to compare these kinases requirements with the ones involved in caveosomes and clathrin-coated pathways.This project also aims at testing the physiol ogical importance of this caveolar-endocytic pathway in lipid droplet storage in vivo. Thus, we will identify lipid species able to stimulate association of caveolins with lipid bodies (starting from unstimulated conditions where caveolin and adipophilin d ont co-localize). We will in this case screen for induction of yellow colour. The physiological contribution of this pathway in nutrients intracellular storage will be evaluated by measuring concentrations of these lipids candidates in fat bodies isolated from animal models for metabolic syndrome. Identification of keys regulators of such a pathway can thus provide new perspectives for the control of lipid storage, a key feature in the battle against obesity.

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