Elevated concentrations of very long chain fatty acids (VLCFAs) may cause cytotoxicity in several cell lines and may be involved in the symptoms of long chain fatty acid oxidation disorders (LCFAODs), a study found.

During the study, the accumulation of certain VLCFAs led to apoptosis in several cell types, including Chinese hamster ovaries (CHOs), neural crest-derived pheochromocytoma cells (PC12), and immortalized adult Fischer rat Schwann cells (IFRS1). Of the VLCFAs tested during the study, they ranged from C16:0 to C25:0. Notably, C20:0 was the most cytotoxic to the cells.

The study was published online in the journal Biochimica et Biophysica Acta: Molecular and Cell Biology of Lipids.

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The VLCFAs were tested at concentrations of 5 uM, 10 uM, and 30 uM, with the cytotoxicity of C20:0 not becoming significant until a concentration of 30 uM for wild-type CHOs. Neural PC12 cells appeared to be much more vulnerable to increased VLCFA concentrations, with significant cytotoxicity being observed at as little as 5 uM concentrations of C20:0.

The IFRS1 cells were much more resistant to C20:0, with cytotoxicity not observed at concentrations up to 30 uM. Additional concentrations were tested for the IFRS1 cells, with a concentration of 150 uM being required before significant cytotoxicity was observed. 

“We found that a certain kind of VLCFAs extensively accumulated in cellular lipids and displayed strong cytotoxicity. We also demonstrated that peroxisomes are pivotal in the detoxification of apoptotic VLCFAs by preventing their accumulation,” the authors said.

CHO cells became more susceptible to VLCFAs if they were peroxisome-deficient (CHO-zp102) or were treated with peroxisomal beta-oxidation inhibitor 10,12-tricosadiynoic acid (TDYA). Both peroxisome-deficient CHOs and TDYA-treated wild-type CHOs showed significant cytotoxicity to C20:0 starting at 5 uM.

Uptake of the VLCFAs was much higher in the wild-type CHOs compared to the peroxisome-deficient cells. However, the accumulation inside the cells was much higher in the CHO-zp102 cells. The VLCFAs tended to accumulate in the cellular lipids. The increased accumulation resulted in morphological changes in DNA in the peroxisome-deficient cells, including condensed chromatin and fragmentation.

Cells were incubated in solutions with VLCFAs, including C16:0, C18:0, C20:0, C22:0, C23:0, C24:0, C25:0, and C26:0. VLCFAs have previously been difficult to dissolve in solution, but the researchers were able to use small amounts of isopropanol to increase their solubility in aqueous solutions.


Ali H, Kobayashi M, Morito K, et al. Peroxisomes attenuate cytotoxicity of very long-chain fatty acids. Biochim Biophys Acta Mol Cell Biol Lipids. Published online December 5, 2022. doi:10.1016/j.bbalip.2022.159259