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Exploring Cellular Pathways of Saturated Fatty Acid Toxicity

Excess long‐chain saturated fatty acids cause cell dysfunction and death, which has been linked to obesity‐related health problems like heart disease and type II diabetes. In this study, we aimed to determine if the incorporation of long‐chain saturated fatty acids into phospholipids in the endoplasmic reticulum (ER) triggers ER stress and lipotoxic cell death. We treated AML12 and NIH3T3 cells with the saturated fatty acid palmitate under conditions that reduced phospholipid synthesis. While culturing cells in the absence of choline decreased phosphatidylcholine synthesis through the Kennedy pathway, choline depletion did not prevent palmitate induction of reactive oxygen species or mitochondrial dysfunction. We also examined palmitate toxicity in the presence of tubercidin, an inhibitor of the PEMT pathway of phosphatidylcholine synthesis and ATK, a phospholipase A2 inhibitor known to decrease phospholipid recycling through the Lands Cycle. Neither inhibitor prevented the changes in mitochondrial function indicative of palmitate toxicity. Therefore, these results do not support the hypothesis that long‐chain saturated fatty acids cause lipotoxicity by changing the cellular composition of phospholipid membranes. Additional experiments are needed to identify lipotoxic pathways.