Length and Unsaturation of Fatty Acids of Phosphatidic Acid Determines the Aggregation Rate of Insulin and Modifies the Structure and Toxicity of Insulin Aggregates.

Phosphatidic acid (PA) is a unique plasma membrane lipid that contains fatty acids (FAs) with different lengths and degrees of unsaturation. Under physiological conditions, PA acts as a second messenger regulating a wide variety of cellular processes. At the same time, the role of PA under pathological conditions, which are caused by an abrupt aggregation of amyloid proteins, remains unclear. In this study, we investigated the effect of PA with different lengths and unsaturation of FAs on insulin aggregation. We found that PA with C16:0 FAs strongly inhibited insulin aggregation, whereas PA with C18:0 FAs accelerated it. Furthermore, PA with unsaturated (C18:1) FAs made the insulin form extremely long and thick fibrils that were not observed for PAs with saturated FAs. We also found that the presence of PA with C16:0 FAs resulted in the formation of aggregates that exerted significantly lower cell toxicity compared to the aggregates formed in the presence of PAs with C18:0 and C18:1 FAs. These results suggest that PA may play a key role in neurodegeneration.