Pathophysiological effects of fatty acids

Elevated plasma free fatty acid levels have been associated with the development of type II diabetes and cardiovascular diseases, and are thought to be present in the obese state. Studies suggest that cellular exposure to free fatty acids can result in intracellular lipid accumulation and lipotoxicity, leading to cellular dysfunction and cell death. In turn, this can promote a range of systemic consequences. This project employed a multifactorial approach to better understand the pathophysiological effects of fatty acids. The effects of the two most common circulating fatty acids, palmitic acid and oleic acid, were investigated on hepatocyte, skeletal myocyte and washed platelet models in vitro. In addition, a systematic review and meta-analysis was conducted to calculate average circulating concentrations of plasma lipid species. This was to determine whether plasma free fatty acids and other lipid species are in fact elevated in obesity. In vitro studies determined that palmitic acid induced cell death in both the hepatocyte and skeletal myocyte models, whilst oleic acid caused intracellular lipid accumulation. However, there was no correlation between lipid accumulation and cell death. In platelets, palmitic acid had no effect. In contrast, oleic acid evoked platelet aggregation that was not characteristic of platelet activation. The meta-analysis determined that circulating plasma free fatty acids are higher in obese subjects than in non-obese subjects and higher yet in type II diabetics. In conclusion, fatty acids exert deleterious effects on a range of cells in vitro, and are raised in the obese state. This lends weight to the proposed association between elevated plasma free fatty acids and comorbidities of obesity, further highlighting the importance of future work to understand the mechanisms responsible.