Very long-chain fatty acids (VLCFAs) are degraded exclusively in peroxisomes, as evidenced by the accumulation of VLCFAs in patients with certain peroxisomal disorders. Although accumulation of VLCFAs is considered to be associated with health issues, including neuronal degeneration, the mechanisms underlying VLCFAs-induced tissue degeneration remain unclear. Here, we report the toxic effect of VLCFA and protective effect of C18: 1 FA in peroxisome-deficient CHO cells. We examined the cytotoxicity of saturated and monounsaturated VLCFAs with chain-length at C20–C26, and found that longer and saturated VLCFA showed potent cytotoxicity at lower accumulation levels. Furthermore, the extent of VLCFA-induced toxicity was found to be associated with a decrease in cellular C18:1 FA levels. Notably, supplementation with C18:1 FA effectively rescued the cells from VLCFA-induced apoptosis without reducing the cellular VLCFAs levels, implying that peroxisome-deficient cells can survive in the presence of accumulated VLCFA, as long as the cells keep sufficient levels of cellular C18:1 FA. These results suggest a therapeutic potential of C18:1 FA in peroxisome disease and may provide new insights into the pharmacological effect of Lorenzo's oil, a 4:1 mixture of C18:1 and C22:1 FA.

极长链脂肪酸 (VLCFA) 仅在过氧化物酶体中降解，患有某些过氧化物酶体疾病的患者中 VLCFA 的积累证明了这一点。尽管 VLCFA 的积累被认为与健康问题（包括神经元变性）有关，但 VLCFA 引起的组织变性的机制仍不清楚。在这里，我们报告了 VLCFA 的毒性作用和 C18:1 FA 在过氧化物酶体缺陷的 CHO 细胞中的保护作用。我们检查了链长为 C20-C26 的饱和和单不饱和 VLCFA 的细胞毒性，发现较长和饱和的 VLCFA 在较低的积累水平下表现出有效的细胞毒性。此外，发现 VLCFA 诱导的毒性程度与细胞 C18:1 FA 水平的降低有关。值得注意的是，补充 C18:1 FA 可以有效地挽救细胞免于 VLCFA 诱导的细胞凋亡，而不会降低细胞 VLCFA 水平，这意味着，只要细胞保持足够的细胞 C18 水平，过氧化物酶体缺陷的细胞就可以在积累的 VLCFA 存在的情况下存活。 ：1 FA。这些结果表明 C18:1 FA 在过氧化物酶体疾病中具有治疗潜力，并可能为洛伦佐油（C18:1 和 C22:1 FA 的 4:1 混合物）的药理作用提供新的见解。