Dysregulated lipogenesis leads to accumulation of toxic substrates that cause neuron degeneration, loss of myelin, and/or OL death. A balanced lipid ratio is crucial for the function and health of OLs. For instance, n-3 polyunsaturated fatty acids (n-3-FA) are pro-resolving lipid mediators. N-3-FA are produced from n-6-FA via Fat-1. Efficient conversion in Fat-1 controls low levels of n-6/n-3, which support OL generation during remyelination, although in part through regulation of microglial inflammation115. Moreover, extracellular lipids can also have toxic effects on OLs. Long-chain saturated free fatty acids (FFAs) produced by reactive astrocytes promote OL death in culture116. Oxidised forms of cholesterol (oxysterols) which accumulate in aging and AD promote OL death117. In addition, oxidized phosphatidyl cholines—markers of oxidative stress—are detected in MS lesions, mediate OL death in culture, and induce demyelination when injected in vivo118.
