Medium-chain fatty acids can efficiently protect very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency cells against antioxidant depletion induced by metabolic stress, according to a new study presented at the 2022 lecture series of the International Network for Fatty Acid Oxidation Research and Management (INFORM).

According to Martin Lund, MSc, PhD, from the Department of Clinical Medicine at Aarhus University and Aarhus University Hospital in Denmark, C8/C7 treatment may facilitate energy production in these cells. It is also essential for maintaining antioxidant defenses and reducing oxidative stress burden during metabolic stress.

VLCAD deficiency is the most common form of long-chain fatty acid oxidation disorder (LCFAOD). It is characterized by lipotoxicity and oxidative stress, which can be triggered by fasting, physical activity, and infections.


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Read more about the etiology of LCFAOD. 

Standard treatment involves medium-chain triglycerides (C8) to bypass the metabolic block of long-chain fatty acid oxidation. But, recent studies have shown that treatment with triheptanoin (C7) can lead to better outcomes.

Dr. Lund and colleagues had previously shown that exposing cells from patients with VLCAD deficiency grown in culture to metabolic stress led to the depletion of glutathione (GSH), an important cellular antioxidant, and therefore worsened oxidative stress and decreased cell survival.  Here, the researchers investigated whether C7 and C8 can protect these cells against antioxidant depletion.

They did this using dermal fibroblast cells from healthy controls and 6 patients with VLCAD deficiency. They pretreated the cells with a medium low in glutamine 96 hours with or without C8 or C7. They then subjected the cells to metabolic stress (high temperature) for 96 hours without renewing their growth medium. This corresponded to a fasting condition. 

The researchers then harvested the cells and measured their Krebs cycle activity as well as their GSH levels and viability. The results showed that C8/C7 corrected the activity of citrate synthase and the depletion of GSH in patient cells as well as rescuing their viability. 

Now, future studies are necessary to qualify the clinical relevance of these findings, Dr. Lund said.

Reference

Lund M, Heaton R, Hargreaves I, Gregersen N, Techn L, Olsen RKJ. Odd- and even-numbered medium-chained fatty acids protect against glutathione depletion in very long-chain acyl-CoA dehydrogenase deficiency (VLCADD). Lecture presented as part of International Network for Fatty Acid Oxidation Research and Management (INFORM) 2022 lecture series: February 14, 2022; Virtual.