Changes in Membrane Organization upon Spontaneous Insertion of 2-Hydroxylated Unsaturated Fatty Acids in the Lipid Bilayer

Abstract

Recent research regarding 2-hydroxylated fatty acids (2OHFAs) showed clear evidence of their benefits in the treatment of cancer, inflammation, and neurodegenerative disorders such as Alzheimer's disease. Monolayer compressibility isotherms and isothermal titration calorimetry of 2OHFA (C18-C22) in phosphatidylcholine/phosphatidylethanolamine/sphingomyelin/cholesterol (1:1:1:1 mole ratio), a mixture that mimics the composition of mammalian plasma membrane, were performed to assess the membrane binding capacity of 2OHFAs and their natural, nonhydroxylated counterparts. The results show that 2OHFAs are surface-active substances that bind membranes through exothermic, spontaneous processes. The main effects of 2OHFAs are a decrease in lipid order, with a looser packing of the acyl chains, and a decreased dipole potential, regardless of the 2OHFAs' relative affinity for the lipid bilayer. The strongest effects are usually observed for 2-hydroxyarachidonic (C20:4) acid, and the weakest one, for 2-hydroxydocosahexaenoic acid (C22:6). In addition, 2OHFAs cause increased hydration, except in gel-phase membranes, which can be explained by the 2OHFA preference for membrane defects. Concerning the membrane dipole potential, the magnitude of the reduction induced by 2OHFAs was particularly marked in the liquid-ordered (lo) phase (cholesterol/sphingomyelin-rich) membranes, those where order reduction was the smallest, suggesting a disruption of cholesterol-sphingolipid interactions that are responsible for the large dipole potential in those membranes. Moreover, 2OHFA effects were larger than for both lo and ld phases separately in model membranes with liquid disordered (ld)/lo coexistence when both phases were present in significant amounts, possibly because of the facilitating effect of ld/lo domain interfaces. The specific and marked changes induced by 2OHFAs in several membrane properties suggest that the initial interaction with the membrane and subsequent reorganization might constitute an important step in their mechanisms of action.

Inflammatory responses to secondary organic aerosols (SOA) generated from biogenic and anthropogenic precursors

“…While there are no prior studies involving pentadecane oxidation products, it is expected that the oxidation products will be similar to those reported in the oxidation of dodecane (i.e., same functionalities with a longer carbon chain; Loza et al, 2014). It is therefore likely that pentadecane oxidation products resemble long chain fatty acids and could potentially insert into the cell membrane (Loza et al, 2014), as previous studies have shown that fatty acids can feasibly insert into the cell membrane bilayer (Khmelinskaia et al, 2014;Cerezo et al, 2011). This insertion could potentially affect membrane fluidity, which is known to affect cell function substantially although the specific effect depends strongly on the particular modification and cell type of interest (Baritaki et al, 2007;Spector and Yorek, 1985).…”

The anti-tumor drug 2-hydroxyoleic acid (Minerval) stimulates signaling and retrograde transport

“…In line with the ricin data, the retrieval of CIMPR was slightly stimulated by treatment with OHOA (Supplementary Figure S10). Furthermore, as OHOA is known to induce changes in membrane microdomain organization [9], and lipid raft integrity is important for proper retrograde transport of glycosphingolipid-binding cargo, such as Shiga toxin (Stx) [31] and cholera toxin [32], we wanted to know whether treatment with OHOA would alter the retrograde transport of Stx. Stx transport to the Golgi was not stimulated by OHOA, but rather reduced (Supplementary Figure S11).…”

The Dipole Potential Modifies the Clustering and Ligand Binding Affinity of ErbB Proteins and Their Signaling Efficiency

“…Since the dipole potential is higher in lipid rafts than in the rest of the membrane 33 , this phenomenon may activate receptor tyrosine kinases in cancer cells. 2-hydroxylated unsaturated fatty acids have been shown to decrease the dipole potential and to have beneficial effects in the treatment of cancer and inflammatory diseases implying that attenuation of signaling upon lowering the dipole potential may even have therapeutic implications 50 .…”