Medium-chain fatty acids can power the antioxidant system and protect cellular viability during metabolic stress in very long chain acyl-coenzyme A (CoA) dehydrogenase (VLCAD) deficiency. This is according to a new study published in the journal Biochimica et Biophysica Acta (BBA) – Molecular and Cell Biology of Lipids

Myopathic symptoms that remain in patients with VLCAD deficiency, a type of long chain fatty acid oxidation disorder (LCFAOD), following triheptanoin treatment, therefore cannot be linked to heptanoate’s inability to protect against antioxidant depletion, Rikke Olsen, PhD, of the Aarhus University Hospital in Denmark, and colleagues noted.

It is known that metabolic stress increases the oxidative burden in VLCAD-deficient cell lines and depletes glutathione, which is an antioxidant, the study authors said.

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Read more about the types of LCFAOD

The investigators set out to address whether medium-chain fatty acids can protect against glutathione depletion during metabolic stress in VLCAD-deficient cells. The researchers modulated the concentration of medium-chain fatty acids in the culture media. They used both even- and odd-numbered medium-chain fatty acids to explore the effect of differences in the anaplerotic capacity of the medium-chain fatty acids. 

They found that the concentration of medium-chain fatty acids affected the levels of glutathione that were retained during metabolic stress in VLCAD-deficient cell lines. Lower levels of glutathione are associated with decreased cellular viability. The addition of heptanoate and octanoate to the culture medium could both rescue this reduced viability in a dose-dependent manner. 

The researchers also found that the addition of a peroxisome proliferator-activated receptor agonist worsened stress-related glutathione depletion and reduced viability even further. In this case, higher concentrations of fatty acids were needed to restore glutathione levels and cellular viability.

“Both odd- and even-numbered medium-chain fatty acids efficiently protect VLCAD deficient cells against metabolic stress-induced antioxidant depletion,” the study authors concluded.


Lund M, Heaton R, Hargreaves I, et al. Odd- and even-numbered medium-chained fatty acids protect against glutathione depletion in very long-chain acyl-CoA dehydrogenase deficiency. Biochim Biophys Acta Mol Cell Biol Lipids. Published online November 7, 2022. doi:10.1016/j.bbalip.2022.159248