Medium branched-chain fatty acids could be a viable anaplerotic treatment option for long-chain fatty acid oxidation disorders (LCFAOD), according to a new study published in the Journal of Inherited Metabolic Disease.

LCFAOD can be life-threatening, even with optimum care, because fatty acid oxidation is the main source of energy for the heart and is essential for the function of skeletal muscles. 

There are 6 main types of LCFAODs. These are carnitine palmitoyltransferase I (CPT I) deficiency, carnitine-acyl-carnitine translocase (CACT) deficiency, carnitine palmitoyltransferase II (CPT II) deficiency, very long-chain acyl-coenzyme A (CoA) dehydrogenase (VLCAD) deficiency, long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency, and trifunctional protein (TFP) deficiency. Each type is caused by a mutation encoding a different enzyme involved in the β-oxidation of long-chain fatty acids.


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In the present study, a team of researchers led by Al-Walid Mohsen, PhD, from the University of Pittsburgh tested medium branched-chain fatty acids as potential anaplerotic treatments in fibroblasts obtained from patients with CPT II deficiency, VLCAD deficiency, LCHAD deficiency, and TFP deficiency.

The researchers treated the cells with C7, 2,6-dimethylheptanoic acid (dMC7), 6-amino-2,4-dimethylheptanoic acid (AdMC7), or 4,8-dimethylnonanoic acid (dMC9). In fibroblasts treated with branched-chain fatty acids, the tricarboxylic acid profile improved compared to those treated with C7.

Moreover, in VLCAD-, LCHAD-, and TFP-deficient cells treated with AdMC7, the intracellular propionate was higher than in those treated with C7.

In CPT II- and VLCAD-deficient cells, AdMC7 treatment led to higher succinate levels than in those treated with C7. Additionally, malate and glutamate levels were higher in all types of cells that were treated with AdMC7 than in those treated with C7.

The researchers concluded, “The results provide the impetus to further evaluate and consider branched-chain fatty acids as viable anaplerotic therapy for fatty acid oxidation disorders and other diseases.”

Reference

Karunanidhi A, Van’t Land C, Rajasundaram D, Grings M, Vockley J, Mohsen AW. Medium branched chain fatty acids improve the profile of tricarboxylic acid cycle intermediates in mitochondrial fatty acid β-oxidation deficient cells: a comparative study. J Inherit Metab Dis. Published online January 25, 2022. doi:10.1002/jimd.12480