Different effects of Lorenzo's oil components against very long-chain fatty acid-induced endoplasmic reticulum stress in peroxisome-deficient CHO cells

Adrenoleukodystrophy (ALD) is an X-linked peroxisomal disorder caused by mutations in the ABCD1 gene, leading to the accumulation of very long-chain fatty acids (VLCFAs). The accumulation of saturated VLCFAs, such as C24:0 and C26:0, is believed to impair myelination. A mixture of C18:1 (oleic acid) and C22:1 (erucic acid), known as Lorenzo's oil, has been used to reduce these saturated VLCFAs. However, despite lowering saturated VLCFA levels, Lorenzo's oil proved ineffective in preventing neurological symptoms. Previously, we found that VLCFA-induced apoptosis is prevented by C18:1 supplementation in peroxisome-deficient Chinese Hamster Overy (CHO) cells. In this study, we investigated the mechanism underlying the rescue effect of C18:1 and examined the effect of C22:1, another component of Lorenzo's oil. Supplementation with C18:1 completely rescued the cells from VLCFA-induced apoptosis. In contrast, C22:1 enhanced VLCFA cytotoxicity and diminished the protective effect of C18:1. We found that VLCFA-induced apoptosis is mediated via the endoplasmic reticulum (ER) stress response possibly by disruption of ER structure, whereas C18:1 attenuated this ER stress. Quantitative lipidomics revealed that VLCFAs were predominantly incorporated into phosphatidylcholine (PC), accompanied by a significant reduction in PC species containing C18:1. Among these, PC 36:2 (18:1/18:1) showed a pattern of change that correlated with cellular viability. These results indicate that C18:1, but not C22:1, protects peroxisome-deficient CHO cells by ameliorating the ER stress response, likely through improving ER structure distorted by VLCFA accumulation.