― 269 ―the redistribution of VLCFAs into less harmful lipid pools. Importantly, our results raise concerns regarding the cytotoxic effects of C22:1, a key component of Lorenzo’s oil, and suggest that alternative formulations excluding C22:1 may be more beneficial. While our cell model provides valuable insights into VLCFA metabolism and toxicity, FA composition in human tissues may differ significantly. Moreover, tissues typically affected in peroxisomal disorders are nerve tissues composed of myelinated neurons. The difficulty in the development of therapeutics for prevention of demyelinating neurodegeneration in ALD is that ABCD1-deficient mice do not exhibit neuropathy like humans ALD. In other words, there are no animal models for evaluation of potential ALD therapeutics. The fact that C18:1 level is a critical factor for cellular fate suggests that a decrease in C18:1 is a key factor in the propagation of ER stress response leading to the demyelination of the disease. To develop a medicinal oil for ALD patients, it is imperative to determine the relationship between the decrease in C18:1 and the onset of neurodegeneration in ALD. AcknowledgmentsThis study was partly supported by Chugai Foundation for Innovative Drug Discovery Science (C-FINDs)(to H.A. and T.T.). We appreciate Dr. Kohei Nishino for providing technical assistance in the analysis of lipidomics data.References1. Morito K., Shimizu R., Ali H., Shimada A., Miyazaki T., Takahashi N., Rahman M.M., Tsuji K., Shimozawa N., Nakao M., Sano S., Azuma M., Nanjundan M., Kogure K. and Tanaka T.: Molecular species profiles of plasma ceramides in different clinical types of X-linked adrenoleukodystrophy. J. Med. Invest., 70, 403-410 (2023).2. Ali H., Morito K., Hasi R.Y., Aihara M., Hayashi J., Kawakami R., Kanemaru K., Tsuchiya K., Sango K. and Tanaka T.: Characterization of uptake and metabolism of very long-chain fatty acids in peroxisome-deficient CHO cells. Biochim. Biophys. Acta, 1867, 159088 (2022).3. Ali H., Kobayashi M., Morito K., Hasi R.Y., Aihara M., Hayashi J., Kawakami R., Tsuchiya K., Sango K. and Tanaka T.: Peroxisomes attenuate cytotoxicity of very long-chain fatty acids. Biochim. Biophys. Acta, 1868, 159259 (2023).4. Ali H., Yamanishi M., Sunagawa K., Kumon M., Hasi R.Y., Aihara M., Kawakami R. and Tanaka T.: Protective effect of oleic acid against very long-chain fatty acid-induced apoptosis in peroxisome-deficient CHO cells. Biochim. Biophys. Acta, 1869, 159452 (2024).5. Rizzo W.B., Watkins P.A., Phillips M.W., Cranin D., Campbell B. and Avigan J.: Adrenoleukodystrophy: oleic acid lowers fibroblast saturated C22–26 fatty acids. Neurol., 36, 357–361 (1986).6. Bligh E.G. and Dyer W.J.: A rapid method of total lipid extraction and purification. Can. J. Biochem. Physiol., 37, 911–917 (1959).7. Kiyokage E., Ichikawa S., Horie S., Hayashi S. and Toida K.: Effects of estradiol on dopaminergic synapse formation in the mouse olfactory bulb. J. Comp. Neuro., 531, 528–547 (2023).
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