How the brain fights fatty acids' toxicity.

Neurons spurn hydrogen-rich fatty acids for energizing oxidative ATP synthesis, contrary to other cells. This feature has been mainly attributed to a lower yield of ATP per reduced oxygen, as compared to glucose. Moreover, the use of fatty acids as hydrogen donor is accompanied by severe β-oxidation-associated ROS generation. Neurons are especially susceptible to detrimental activities of ROS due to their poor antioxidative equipment. It is also important to note that free fatty acids (FFA) initiate multiple harmful activities inside the cells, particularly on phosphorylating mitochondria. Several processes enhance FFA-linked lipotoxicity in the cerebral tissue. Thus, an uptake of FFA from the circulation into the brain tissue takes place during an imbalance between energy intake and energy expenditure in the body, a situation similar to that during metabolic syndrome and fat-rich diet. Traumatic or hypoxic brain injuries increase hydrolytic degradation of membrane phospholipids and, thereby elevate the level of FFA in neural cells. Accumulation of FFA in brain tissue is markedly associated with some inherited neurological disorders, such as Refsum disease or X-linked adrenoleukodystrophy (X-ALD). What are strategies protecting neurons against FFA-linked lipotoxicity? Firstly, spurning the β-oxidation pathway in mitochondria of neurons. Secondly, based on a tight metabolic communication between neurons and astrocytes, astrocytes donate metabolites to neurons for synthesis of antioxidants. Further, neuronal autophagy of ROS-emitting mitochondria combined with the transfer of degradation-committed FFA for their disposal in astrocytes, is a potent protective strategy against ROS and harmful activities of FFA. Finally, estrogens and neurosteroids are protective as triggers of ERK and PKB signaling pathways, consequently initiating the expression of various neuronal survival genes via the formation of cAMP response element-binding protein (CREB).