Targeting surface voids to counter membrane disorders in lipointoxication-related diseases.
J Cell Sci
; 129(12): 2368-81, 2016 06 15.
Article
em En
| MEDLINE
| ID: mdl-27142833
ABSTRACT
Saturated fatty acids (SFA), which are abundant in the so-called western diet, have been shown to efficiently incorporate within membrane phospholipids and therefore impact on 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 ß-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 or void-sensing proteins required for vesicular budding, a central cellular process that is precluded under SFA accumulation. Taken together, 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.
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Base de dados:
MEDLINE
Assunto principal:
Saccharomyces cerevisiae
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Membrana Celular
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Lipídeos
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article