Pharmacological characterization of the cytoprotective effects of polyunsaturated fatty acids in insulin-secreting BRIN-BD11 cells

BACKGROUND AND PURPOSE Free fatty acids are important metabolic fuels for mammalian cells but, recently, it has become clear that they can also fulfil signalling functions, which are independent of their metabolic fate. We are investigating the ability of unsaturated free fatty acids to exert a cytoprotective response during exposure of insulin-secreting cells to toxic stimuli. The majority of earlier studies have focussed on monounsaturated fatty acids but this has now been extended to define the structural requirements of the cytoprotective effects of polyunsaturated species. EXPERIMENTAL APPROACH Clonal rat insulin-secreting cell lines, BRIN-BD11 or INS-1, were exposed to fatty acids or their derivatives complexed with BSA and the viability of the cells was analysed by flow cytometry after staining with propidium iodide. KEY RESULTS A variety of polyunsaturated fatty acids with chain lengths between C18-C22 attenuated the cytotoxic actions of the saturated fatty acid, palmitate (C16:0) in BRIN-BD11 and INS-1 cells. These effects were dose-dependent and displayed potencies that were much higher than those achieved with monounsaturated fatty acids. Methyl esters of the polyunsaturates were also effective. The cytoprotective responses were not altered by incubation of cells with inhibitors of cyclooxygenase or lipoxygenase enzymes although they were antagonized dose-dependently by arachidonyltrifluoromethylketone (AACOCF(3)). CONCLUSIONS AND IMPLICATIONS The results are consistent with the involvement of a specific fatty acid binding site having loose, but defined, structural criteria, in mediating the cytoprotective effects of unsaturated fatty acids. AACOCF(3) may be of value in defining this site in molecular terms.