Prostaglandins, Leukotrienes and Essential Fatty Acids
How fatty acids of different chain length enter and leave cells by free diffusion
Introduction
The ongoing debate about the mechanisms by which long-chain fatty acids (LCFA) cross cell membranes is fuelled in part by the fundamental assumption that transport must be tightly controlled to achieve regulation of uptake and metabolism. Thus, a simple mechanism such as free diffusion for transport of basic metabolites like LCFA does not seem to be a plausible one. Moreover, several putative fatty acid transporters in the plasma membrane have been identified over the last decade. As stated by Zakim, “The two opposing views about the mechanism for cellular uptake of fatty acids reflect, I believe, the biases and tension between the idea that all events in cells have complex biological basis versus the idea that this not need be so.” [1]. A more provocative general statement in biophysics was made by Sackmann: “Nature would not be stupid, not using simple mechanisms” [2]. There are several compelling reasons to argue that free diffusion is the main, if not sole, mechanism for membrane transport of LCFA. Since polyunsaturated fatty acids (PUFA) have similar biophysical properties as other LCFA, the arguments discussed below apply also for them. More extensive recent reviews have been published elsewhere by us [3], [4], [5] and others [6], [7], [8], [9], [10].
Section snippets
Argument 1: Overton rule
The first argument is a 100-year-old principle of the membrane permeability of any molecule: the more hydrophobic, the higher its membrane permeability [11]. This so-called “Overton rule” is illustrated in Fig. 1A. A concentration gradient of molecular species X dissolved in water exists across a membrane. The species binds at the water-membrane interface with partition equilibrium constant Kp=Xb/X=kon/koff, where Xb and X represent the concentrations of the bound and unbound species. kon and k
Discussion
Facilitated transport through biological membranes is a necessary mechanism for the large family of ions, charged metabolites like amino acids, lactate and pyruvate as well as large hydrophilic non-electrolytes (glucose). The values of the permeability constants for few selected molecules in Table 1 clearly demonstrate why. In the case of water, the discovery of aquaporin as transporter in specific tissues where diffusion does not suffice was originally considered revolutionary but is nowadays
Conclusion
We have argued that FA cross protein-free phospholipid bilayers very rapidly (t1/2<1 s). They also cross the plasma membrane of cells rapidly both in intact cells and in isolated membrane vesicles [35]. In the context of the lipid phase of biological membranes, where FA bind with high affinity and rapid kinetics, and where the energy barrier for translocation of the uncharged carboxyl is low [75], putative LCFA transport proteins do not fulfill classic requirements for transport proteins.
If
Acknowledgment
We thank Christian Haass, David Zakim, Frits Muskiet, Berthold Koletzko, Reinhart Heinrich and Klaus Beyer for stimulating discussions.
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