Abstract
Medium-chain fatty acids (mc-FAs) are currently applied in the treatment of long-chain fatty acid oxidation disorders (lc-FAOD) characterized by impaired β-oxidation. Here, we performed lipidomic and proteomic analysis in fibroblasts from patients with very long-chain acyl-CoA dehydrogenase (VLCADD) and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHADD) deficiencies after incubation with heptanoate (C7) and octanoate (C8). Defects of β-oxidation induced striking proteomic alterations, whereas the effect of treatment with mc-FAs was minor. However, mc-FAs induced a remodeling of complex lipids. Especially C7 appeared to act protectively by restoring sphingolipid biosynthesis flux and improving the observed dysregulation of protein homeostasis in LCHADD under control conditions.
Highlights
Lc-FAOD can be diagnosed though newborn screening (NBS) due to the accumulation of diseasespecific acylcarnitine species that can be identified via tandem mass spectrometry [1,2]
Long-chain fatty acid oxidation disorders are a group of rare inborn errors of metabolism leading to severe energy deficits that may result in metabolic decompensation, especially during situations of increased energy demand [1]
In this work we show that even and odd medium-chain fatty acids such as C7 and C8, which are commonly applied in the treatment of Long-chain fatty acid oxidation disorders (lc-FAOD) [3,4,5,32], do represent a source of energy and induce disease- and treatment-specific alteration in the lipidomic and proteomic profile when they are supplemented to long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHADD) and very long-chain acyl-CoA dehydrogenase (VLCADD) fibroblasts
Summary
Long-chain fatty acid oxidation disorders (lc-FAOD) are monogenic inherited diseases affecting the mitochondrial β-oxidation of long-chain fatty acids (lc-FA). Lc-FAOD can be diagnosed though newborn screening (NBS) due to the accumulation of diseasespecific acylcarnitine species that can be identified via tandem mass spectrometry [1,2]. During situations of increased energy demand, when the organism mostly relies on β-oxidation for energy production, lc-FA cannot enter the β-oxidation cycle resulting in severe energy deficiency and in the accumulation of toxic metabolites. Treatment recommendations point at preventing catabolism and include avoidance of fasting, a fatrestricted diet and the application of medium-chain fatty acid (MCT oil) [3,4].
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