La familia de los recptores de lipogroteínas de baja densidad en Drosophila. Funciones en desarrollo y en la adquisición celular de lípidos neutros

Resumen

Low Density Lipoprotein Receptors (LDLRs) are a family of evolutionarily conserved proteins with related functions and structure. They are involved in the endocytosis and clearance of multiple ligands, including cholesterol rich LDL. Moreover, some members also have signaling capacity. Orthologues of these genes are present in all metazoans including Drosophila melanogaster. In this thesis we have studied four member of the LDLR family in this organism: ldlr-related protein 1 (lrp1), megalin (mgl) and lipophorin receptors 1 and 2 (lpr1 and lpr2). Our characterization of lrp1 indicates that this gene is involved in the growth and patterning of the Drosophila wing. Genetic interaction experiments suggest that lrp1 modulates TGF-ß signaling during vein specification. In the wing imaginal discs, lpr1 appears to modulate the Dpp distribution gradient. Drosophila mgl is essential for the deposition of a proper adult wing cuticle, the mutants show incomplete expansion of the wings and altered cuticle structure. Finally, our results indicate that lpr1 and lpr2 are involved in lipid metabolism in the fly. Lipids are transported through the blood or the insect hemolymph as small particles known as lipoproteins to redistribute energy and metabolites between sites of absorption, storage, and catabolism in a complex homeostatic equilibrium. We show in this thesis that lpr1 and lpr2 are essential for the efficient uptake and accumulation of neutral lipids by oocytes and cells of the imaginal discs. Females lacking the lpr2 gene lay eggs with low lipid content and have reduced fertility, revealing a central role for lpr2 in mediating Drosophila vitellogenesis. lpr1 and lpr2 are transcribed into multiple isoforms. Interestingly, only a subset of these isoforms containing a particular LDLR type A module mediate neutral lipid uptake. Expression of these isoforms induces the extracellular stabilization of lipophorins. Furthermore, our data indicate that endocytosis of the lipophorin receptors is not required to mediate the uptake of neutral lipids. These findings suggest a model where lipophorin receptors promote the extracellular lipolysis of lipophorins. This model is reminiscent of the lipolytic processing of triglyceride-rich lipoproteins that occurs at the mammalian capillary endothelium, suggesting an ancient role for LDLR-like proteins in this process. The work presented in this thesis points to Drosophila as an excellent experimental model to study lipid uptake in peripheral tissues as well as possible regulators of this process that could be involved in energy partitioning.