Targeting surface voids to counter membrane disorders in lipointoxication-related diseases

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 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 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.

PackMem: A Versatile Tool to Compute and Visualize Interfacial Packing Defects in Lipid Bilayers

“…In previous work (7,13,15,28), the error on p was determined from the error on the linear fit of the logarithmic plot, thus considering the logarithmic value of p(A). However, we believe that an error determined by block averaging, as reported here, is more reliable, and we encourage the users to follow this procedure in the future.…”

“…We have recently developed a computational approach to identify lipid-packing defects based on mapping of the membrane surface according to a Cartesian grid. This method has allowed us to investigate the effect of various membrane parameters on interfacial properties, including acyl chain mono-and polyunsaturation (8,13,14), membrane curvature (7), and the presence of conical lipids or of molecules against lipointoxication (15). The pivotal role of interfacial voids has been suggested by a number of recent investigations on disparate topics, including membrane remodeling processes such as bending, fusion, and fission (8,(16)(17)(18)(19) as well as the binding of peripheral proteins, disaccharides, and nanoparticles (8,14,20).…”

Glued in lipids: Lipointoxication in cystic fibrosis

“…Many studies have demonstrated that the UPR is activated upon SFA overload, in virtually all cell types, including, among others, pancreatic b-cells [63][64][65], hepatocytes [66], muscle cells [67], adipocytes [68], yeast [69], and, relevant to the present review, bronchial epithelial cells [17,18].…”