title: Partitioning of liquid-ordered/liquid-disordered membrane microdomains induced by the fluidifying effect of 2-hydroxylated fatty acid derivatives.
abstract: Cellular functions are usually associated with the activity of proteins and nucleic acids. Recent studies have shown that lipids modulate the localization and activity of key membrane-associated signal transduction proteins, thus regulating the cell's physiology. Membrane Lipid Therapy aims to reverse cell dysfunctions (i.e., diseases) by modulating the activity of membrane signaling proteins through regulation of the lipid bilayer structure. The present work shows the ability of a series of 2-hydroxyfatty acid (2OHFA) derivatives, varying in the acyl chain length and degree of unsaturation, to regulate the membrane lipid structure. These molecules have shown greater therapeutic potential than their natural non-hydroxylated counterparts. We demonstrated that both 2OHFA and natural FAs induced reorganization of lipid domains in model membranes of POPC:SM:PE:Cho, modulating the liquid-ordered/liquid-disordered structures ratio and the microdomain lipid composition. Fluorescence spectroscopy, confocal microscopy, Fourier transform infrared spectroscopy and differential detergent solubilization experiments showed a destabilization of the membranes upon addition of the 2OHFAs and FAs which correlated with the observed disordering effect. The changes produced by these synthetic fatty acids on the lipid structure may constitute part of their mechanism of action, leading to changes in the localization/activity of membrane proteins involved in signaling cascades, and therefore modulating cell responses.
authors.affiliation: Laboratory of Molecular Cell Biomedicine, University of the Balearic Islands-Lipopharma Therapeutics, S.L., Palma, Spain.
authors.forename: Maitane
authors.initials: M
authors.lastname: Ibarguren
authors.forename: David J
authors.initials: DJ
authors.lastname: López
authors.forename: José A
authors.initials: JA
authors.lastname: Encinar
authors.forename: José M
authors.initials: JM
authors.lastname: González-Ros
authors.forename: Xavier
authors.initials: X
authors.lastname: Busquets
authors.forename: Pablo V
authors.initials: PV
authors.lastname: Escribá
mesh_terms: D000818:Animals; D005227:Fatty Acids / Q000737:chemistry*; D006900:Hydroxylation; D007700:Kinetics; D008563:Membrane Lipids / Q000737:chemistry; D021962:Membrane Microdomains / Q000737:chemistry*; D008856:Microscopy, Fluorescence; D017550:Spectroscopy, Fourier Transform Infrared
chemical_list: D005227:Fatty Acids; D008563:Membrane Lipids
keywords: 1,1′-dioctadecyl-3,3,3′3′-tetramethylindo carbocyanine perchlorate; 1-oleoyl-2(12-((7-nitro-2-1,3-benzoxadioazol-4-yl)amino) dodecan oyl)-sn-glycero-3-phosphoethanola mine; 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine; 2-hydroxy fatty acid; 2-hydroxy-docosahexaenoic acid; 2-hydroxy-stearic acid; 2-hydroxy-α-linolenoic acid; 2-hydroxy-γ-linolenic acid; 2-hydroxyarachidonic acid; 2-hydroxyeicosapentaenoic acid; 2-hydroxylinoleic acid; 2-hydroxyoleic acid; 2OHARA; 2OHDHA; 2OHEPA; 2OHFA; 2OHLA; 2OHOA; 2OHSA; 2OHαLNA; 2OHγLnA; ARA; Cho; DHA; DMSO; DRM; DiI; EPA; Fatty acid; GM1; GUV; HSP; LA; LUV; Ld; Lipid raft; Lo; MLV; Membrane Lipid Therapy; Membrane fluidity; Membrane lipids; Membrane structure; NBD-PE; OA; PE; POPC; SA; SM; arachidonic acid; cholesterol; detergent resistance membrane; dimethyl sulfoxide; docosahexaenoic acid; eicosapentaenoic acid; giant unilamellar vesicle; heat shock protein; large unilamellar vesicles; linoleic acid; liquid-disordered; liquid-ordered; monosialotetrahexosyl ganglioside; multilamellar vesicles; oleic acid; phosphatidylethanolamine; sphingomyelin; stearic acid; α-linolenic acid; αLnA; γ-linolenic acid; γLnA