Lipotoxicity in adrenoleukodystrophy Size matters!

X-linked adrenoleukodystrophy (ALD) is the most common leukodystrophy with a birth incidence of 1:14,700. ALD is characterized by impaired beta-oxidation and enhanced elongation of very long-chain fatty acids (VLCFA) due to a defect in the peroxisomal transmembrane protein ABCD1. The first part of this theses is focused on improving the diagnosis of ALD. To this end, a method is described which can be used to measure beta-oxidation and de novo synthesis in living cells by using stable-isotope labelled substrates. Diagnosing women with ALD can be challenging since 20% have normal VLCFA plasma levels. This thesis shows that C26:0-lysoPC (the biomarker currently used to detect ALD in newborn screening programs) is a more accurate biomarker to diagnose women with ALD. Furthermore, C26:0-carnitine was identified as a good biomarker for ALD in an ALD mouse model and adult male ALD patients but failed as a biomarker for newborns and women with ALD.
The exact mechanism behind VLCFA toxicity has not been resolved at the cellular level yet. This thesis shows that exposure to VLCFA activates the endoplasmic reticulum (ER) stress response and causes lipoapoptosis in fibroblasts from ALD patients. Interestingly, only saturated VLCFA but not mono-unsaturated VLCFA activate the ER stress response. Via activation of stearoyl-CoA desaturase 1, it is possible to redirect the saturated VLCFA synthesis towards the mono-unsaturated VLCFA synthesis. This results in a normalization of the saturated VLCFA levels in fibroblasts from ALD patients.