Designer triglycerides: A practical approach to deliver alternative fatty acids to treat fatty acid oxidation disorders


Presented By:

Al-Walid Mohsen, PhD1,2,* ,Anuradha Karunanidhi, MS1, Clinton Van’t Land PhD1, and Ahmad AlodaibPhD1, Jerry Vockley, MD, PhD1,2

1Department of Pediatrics and 2Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA,

*Correspondence email:

Background: Fatty acid -oxidation (FAO) is the major source of energy for the heart and is critical for skeletal muscles especially during physiologic stress. Symptoms of FAO disorders include stress-related hypoketotic hypoglycemia or Reye-like syndrome, cardiac conduction abnormalities, arrhythmias, cardiomyopathy, muscle weakness, and rhabdomyolysis. Sudden death can occur. MCT oils bypass the need for the long chain FAO in some disorders but patients are still at risk for rhabdomyolysis and late onset cardiomyopathy. Despite apparent success of triheptanoin in reducing the incidence of hypoglycemia and cardiomyopathy in VLCAD patients, rhabdomyolysis requiring hospitalization still persists and additional therapy to prevent the heterogeneous symptoms of FAODs is still needed.

Methods: Fibroblasts from patients with defects in CPT II, VLCAD, LCHAD, and TFP were cultured (n=6) in media with lipid stripped FBS. The cells were treated with heptanoic (C7), 2,6-dimethylheptanoic (dMC7), and 4,8-dimethylnonanoic (dMC9) acids for 72 hr. C2-, C3, and C4DC-carnitines were tested in media and TCA cycle intermediates were tested in cells.

Results: CPT II, VLCAD, LCHAD, and TFP deficient cells treated with dMC7 and dMC9 had increased presence of C4DC-carnitine compared to C7. C2-carnitine was increased in VLCAD, LCHAD, and TFP. Intracellular malate was higher in VLCAD, LCHAD, and TFP cell lines using dMC7 and dMC9 compared to C7. Levels of other TCA metabolites indicate patient cells also improved with treatment with the branched medium chain fatty acids versus C7.

Discussion: Alternative medium branched chain fatty acids have shown improvement in metabolite profiles suggesting possible advantage over C7 as triglycerides to treat these diseases. Since the suggested alternative derivates are, or lead to, natural physiological intermediates, testing their triglyceride version in clinical trials should feasible in the near future.

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