Triglyceride Blisters in Lipid Bilayers: Implications for Lipid Droplet Biogenesis and the Mobile Lipid Signal in Cancer Cell Membranes

Abstract

Triglycerides have a limited solubility, around 3%, in phosphatidylcholine lipid bilayers. Using millisecond-scale course grained molecular dynamics simulations, we show that the model lipid bilayer can accommodate a higher concentration of triolein (TO) than earlier anticipated, by sequestering triolein molecules to the bilayer center in the form of a disordered, isotropic, mobile neutral lipid aggregate, at least 17 nm in diameter, which forms spontaneously, and remains stable on at least the microsecond time scale. The results give credence to the hotly debated existence of mobile neutral lipid aggregates of unknown function present in malignant cells, and to the early biogenesis of lipid droplets accommodated between the two leaflets of the endoplasmic reticulum membrane. The TO aggregates give the bilayer a blister-like appearance, and will hinder the formation of multi-lamellar phases in model, and possibly living membranes. The blisters will result in anomalous membrane probe partitioning, which should be accounted for in the interpretation of probe-related measurements.

Hydrophobic droplets in amphiphilic bilayers: a coarse-grained mean-field theory study

“…Furthermore, the formation of droplets even in our simple model indicates that this might be quite a general phenomenon and that hydrophobic domains such as those seen in the molecular dynamics simulations of Khandelia et al [11] might be observed in a variety of systems.…”

“…We could also study how likely the droplet is to split off from the bilayer, for example by comparing the free energies of the bilayerencapsulated droplet and a system of a droplet covered by a monolayer in coexistence with a bilayer. Finally, droplets formed from a second species of amphiphile could be studied, to bring our calculations closer to the problem of lipid domains in bilayers [11,16]. …”

“…The question then arises of whether this is due to the presence of small lipid domains within the bilayer, the existence of which has also been suggested to explain the formation of the lipid droplets seen in the center of cells [12,13]. Observations of such bilayer domains have indeed been reported in the biophysics literature [14,15], and these structures have recently been seen in molecular dynamics simulations [11]. However, their probable small size and the existence of other lipid domains in the cell complicates the interpretation of experiments, and the issue is not fully resolved [16].…”

Identification of the major functional proteins of prokaryotic lipid droplets

“…The current model of LD biogenesis speculates that LDs are derived from the endoplasmic reticulum (ER) by a process that begins with the accumulation of neutral lipids between the leafl ets of phospholipid bilayers ( 3,19 ). Many studies have attempted to unravel how LDs form and grow, but this hypothesis still lacks direct evidence and the molecular mechanism Abstract Storage of cellular triacylglycerols (TAGs) in lipid droplets (LDs) has been linked to the progression of many metabolic diseases in humans, and to the development of biofuels from plants and microorganisms.…”

Lumenal Lipid Metabolism

“…Because lumenal acylCoA-dependent acylations do occur in the ER, such as ethanol esterification 13 and apoB palmitoylation, [14][15][16] some transporter/ channel-mediated process is likely to exist. To this effect, both N-ethylmaleimide-sensitive acyl-CoA acyltransferasemediated 17,18 and N-ethylmaleimide insensitive but mersalyl 20 Although a plethora of studies have dealt with the mechanism of cytosolic LD formation and composition, [21][22][23][24] information on the biosynthesis of lumenal LDs is limited in comparison. A number of factors potentially regulating formation of cytosolic LDs have been identified, including perilipins 25 and fat storage-inducing transmembrane proteins.…”