Un subgrupo de isoformas de los receptores de lipoforinas de Drosophila melanogaster interacciona con distintas afinidades con las lipoproteinas lipoforina y LTP en la membrana plasmática, mediando así la adquisición celular de lípidos neutros

Abstract

Sedentary lifestyle and new dietary habits are causing a worldwide increase in diseases and conditions related to an unbalanced lipid metabolism, such as atherosclerosis. The core elements of mammalian lipid metabolism and cellular lipid uptake are well understood. One of the key components is the Low Density Lipoprotein Receptors (LDLR), which regulate cholesterol homeostasis. Because of its genetics, Drosophila is becoming a widely used model organism to study disorders associated to metabolic syndrome, such as obesity. However, there are still basic aspects of Drosophila lipid metabolism that we do not understand, hindering its value as a valid model. In this thesis, we uncovered the molecular mechanism that mediates the transfer of lipids from circulating lipoproteins to peripheral tissues like imaginal discs and ovaries in Drosophila. Lipophorin is the major lipid carrier in hemolymph. It interacts with tissues through the lipophorin receptors, homologous to the human LDLR. However, we have demonstrated that this interaction is mostly indirect and transient. In addition to lipophorin, hemolymph also contains the lipoprotein Lipid Transfer Particle (LTP), with the catalytic activity of transferring lipids between lipoproteins and membranes. Here, we show that the lipophorin receptors recruit LTP to the plasma membrane and that this is the key event that triggers the uptake of neutral lipids into cells. This high affinity binding between LTP and the lipophorin receptors requires the LA1 domain, found in a subset of lipophorin receptor isoforms, and is strengthened by a contiguous region of 16 conserved amino acids. This interaction also promotes the extracelullar stabilization of lipophorin in the plasma membranes. These three elements: Lipophorin receptors, LTP and lipophorin, represent a functional intermediate during lipid transfer from lipophorin to cells, a process that does not require the endocytosis of the complex. We also show that the lipophorin receptor isoforms that mediated lipid uptake contain an atypically long signal peptide that induces low levels of translation. We do not know the functional implications of this. Together, our data improves our understanding of a central aspect of lipid metabolism in Drosophila. Interestingly, even though the lipophorin receptors and the human LDLR have related functions and structure, the specific molecular mechanisms involved are diverse. This is a clear example of LDLR family versatility throughout evolution and in different species.