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Am J Pathol. 1979 Nov;97(2):212-21.

Lipid domains in biological membranes: their structural and functional perturbation by free fatty acids and the regulation of receptor mobility. Co-presidential address.


We have studied the interaction of free fatty acids (FFAs) with cell membranes and lipid bilayers by monitoring changes in the emission polarization of the fluorescent probes diphenylhexatriene (DPH) and anilino-naphthalene sulfonate (ANS). We found that the FFAs readily intercalate into membranes and produce significant changes in the packing of the lipid molecules. The membrane alterations could be divided into two patterns: the cis-unsaturated FFAs (designated Group A) disorder the membranes' interior (as reported by DPH) and order the head group region (as reported by ANS); the trans-unsaturated or saturated FFAs (Group B) do not alter the bilayer interior but also order the head group region. Using solution theory, the shift in transition midpoint temperatures as a function of fatty acid type was used to infer that the Group A FFAs partition into fluid domains, while Group B FFAs partition preferentially into gel-like domains. These results are explained in terms of a domain model of membrane lipid structure. Low concentrations of Group A FFAs inhibit the capping of surface immunoglobulin (Ig), whereas no effect was seen with Group B FFAs. The capping inhibition caused by Group A FFAs was reversible with increasing doses of extracellular calcium. Fluorescence photobleaching recovery showed that the Group A FFAs do not inhibit receptor immobilization associated with patch formation but rather inhibit the final energy-dependent movement of the patched receptors into a cap. We have also shown that the Group A FFAs cause a shift in membrane-bound calcium to the lipid phase from probably protein calcium-binding sites. The data have generated a model of receptor mobility invoking a trans-membrane, calcium-binding, receptor-anchoring protein, linked to the cytoskeleton. Inhibition of capping by Group A FFAs is postulated to be due to perturbation of specific lipid domains associated with this protein, such perturbation leading to conformational changes in the protein, and consequent intramembraneous calcium sequestration in the lipid phase, rendering the calcium unavailable for activation of the cytoskeleton.

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