Targeting surface voids to counter membrane disorders in lipointoxication-related diseases
Résumé
Saturated fatty acids (SFA), which are abundant in the so-called Western-diet, have been shown to efficiently incorporate within membrane phospholipids (PL) and therefore impact organelle integrity and function in many cell-types. In the present study, we have developed a yeast-based two-step assay and a virtual screening strategy to identify new drugs able to counter SFA-mediated lipointoxication. The compounds identified here were effective in relieving lipointoxication in mammalian β-cells, one of the main targets of SFA toxicity in humans. In vitro reconstitutions and molecular dynamics simulations on bilayers revealed that these molecules, albeit according to different mechanisms, can generate voids at the membrane surface. The resulting surface defects correlate with the recruitment of loose lipid packing/void-sensing proteins required for vesicular budding, a central cellular process that is precluded under SFA-accumulation. Altogether, the results presented here point at modulation of surface voids as a central parameter to consider in order to counter the impacts of SFA on cell function.