Lipidomic and Proteomic Alterations Induced by Even and Odd Medium-Chain Fatty Acids on Fibroblasts of Long-Chain Fatty Acid Oxidation Disorders

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.

An Altered Sphingolipid Profile as a Risk Factor for Progressive Neurodegeneration in Long-Chain 3-Hydroxyacyl-CoA Deficiency (LCHADD)

“…In LCHADD/MTPD they may, therefore, share the co-responsibility for the specific development of retinopathy and peripheral neuropathy. This hypothesis is supported by the fact that the incubation of fibroblasts of LCHADD patients with medium chain fatty acids, especially heptanoate, avoids the biosynthesis and accumulation of long-chain hydroxy acylcarnitines, contributes to the restoration of the sphingolipid content and profile and makes this similar to those observed in the fibroblasts of healthy controls [8]. In accordance to this hypothesis, Francis et al 2013 reported an improvement in oligodendrocyte survival and myelination in a mouse model of Canavan Disease [70].…”

“…It is therefore conceivable that sequence variants affecting MTP enzyme activity result in an altered cardiolipin profile [7]. At the same time, an aberrant cardiolipin profile reduces mitochondrial fusion and fission processes [18][19][20] and leads to the destabilization of mitochondrial supercomplexes and the dysregulation of energy metabolism [7,8]. Analysis in human fibroblasts has highlighted that the LCHADD induces cardiolipin remodeling with a subsequent profile alteration and incorporation of the non-metabolized C16 fatty acids into cardiolipin species [7].…”

“…However, cardiolipins are not the only lipid class that is subjected to remodeling. Indeed, sphingolipids change in content and profile and are characterized by an upregulation of the biosynthesis of hexosylceramides [8]. In particular, these lipids have been reported as detrimental for other neurodegenerative diseases [54].…”

“…These symptoms specific for LCHADD and MTPD are progressive and cannot be avoided. Studies in the fibroblasts of patients with lc-FAODs have demonstrated that the accumulating fatty acids due to defective β-oxidation are likely involved in remodeling processes leading to an alteration of the profile and content of complex lipids [7,8].…”

Lipidomics—Paving the Road towards Better Insight and Precision Medicine in Rare Metabolic Diseases

“…Moreover, the abnormal PC/PE ratio, the increased levels of plasmalogens and lyso-PL support the theory of inflammatory processes in lc-FAOD. Recently, Alatibi et al showed that the application of saturated medium-chain FA (especially C7) leads to an altered composition of membrane lipids in patient’s fibroblasts, especially observed in LCHADD fibroblasts [ 133 , 139 ]. In addition, treatment with MCFA seemed to be particularly beneficial in fibroblast cell lines of FAOD patients by supporting mitochondrial metabolism and by enabling restoration of the SL metabolic flux, and reducing the protein expression known to be involved in neurodegenerative diseases.…”