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Low density Lipoprotein receptors in development and signalling

Final Activity Report Summary - LDLRDS (Low density lipoprotein receptors in development and signaling)

Proteins of the low density lipoprotein receptor family (LDLRs) have essential biological roles. For example, one of the members of the family, the human LDLR, regulates cholesterol levels in plasma and its mutations lead to familial hypercholesterolemia. Other LDLRs play key roles during the development of organisms and their malfunction is linked to the Donnai-Barrow, facio-oculo-acoustico-renal and osteoporosis pseudoglioma syndromes. All LDLRs are structurally related proteins and more importantly, they are evolutionarily conserved. Thus, we find the same or very similar set of LDLRs in organisms as distant as the fly Drosophila, the nematode, zebrafish or humans. This structural and functional conservation allows us to use simple organisms with powerful genetics like Drosophila to study the functions of LDLRs.

In this project, we have done the initial characterisation of four LDLRs in the fly. Two of these genes, that we called lipophorin receptor 1 and 2, are related to the human LDLR and similarly to it, regulate lipid metabolism. Flies that are mutant for the lipophorin receptors are unable to efficiently mobilise their lipid reserves during starvation. At the cellular level, lipophorin receptors mediate the uptake of lipids from the surrounding hemolyph. Our results validate and increase the usefulness of Drosophila as a model organism to study pathologies related to energy balance regulation, like obesity, diabetes and metabolic syndrome. We have also identified and done the initial genetic and molecular characterisation of the fly lrp1 gene.

Our results show that this gene modulates the activity of the TGF-beta signalling pathway, a key regulator of multiple biological processes that is involved in cancer pathogenesis, neurodegeneration and atherosclerosis. These studies are the foundation for a better understanding of the interplay between LRP1 and TGF- beta.