ω-Oxidation of Very Long-chain Fatty Acids in Human Liver Microsomes (original) (raw)

2006, Journal of Biological Chemistry

X-linked adrenoleukodystrophy (X-ALD) is a severe neurodegenerative disorder biochemically characterized by elevated levels of very long-chain fatty acids (VLCFA). Excess levels of VLCFAs are thought to play an important role in the pathogenesis of X-ALD. Therefore, therapeutic approaches for X-ALD are focused on the reduction or normalization of VLCFAs. In this study, we investigated an alternative oxidation route for VLCFAs, namely-oxidation. The results described in this study show that VLCFAs are substrates for the-oxidation system in human liver microsomes. Moreover, VLCFAs were not only converted into-hydroxy fatty acids, but they were also further oxidized to dicarboxylic acids via cytochrome P450-mediated reactions. High sensitivity toward the specific P450 inhibitor 17-octadecynoic acid suggested that-hydroxylation of VLCFAs is catalyzed by P450 enzymes belonging to the CYP4A/F subfamilies. Studies with individually expressed human recombinant P450 enzymes revealed that two P450 enzymes, i.e. CYP4F2 and CYP4F3B, participate in the-hydroxylation of VLCFAs. Both enzymes belong to the cytochrome P450 4F subfamily and have a high affinity for VLCFAs. In summary, this study demonstrates that VLCFAs are substrates for the human-oxidation system, and for this reason, stimulation of the in vivo VLCFA-oxidation pathway may provide an alternative mode of treatment to reduce the levels of VLCFAs in patients with X-ALD. In mammalian cells, fatty acid oxidation plays a major role in the production of energy, particularly in the heart and skeletal muscle, and is the main energy source during periods of fasting. Both mitochondria and peroxisomes are capable of degrading saturated fatty acids via ␤-oxidation. Short-, medium-, and long-chain saturated fatty acids are degraded predominantly by mitochondria, whereas very long-chain fatty acids (VLCFA, 2 Ͼ22 carbons) are ␤-oxidized exclusively in peroxisomes (1, 2). Moreover, peroxisomes also metabolize certain branched chain fatty acids, bile acid precursors, eicosanoids, and dicarboxylic acids (3).