Origin and Metabolism of VLCFA
Adrenoleukodystrophy is characterized by the inability of cells to metabolize/degrade VLCFA to shorter-chain fatty acids. This results in elevated VLCFA levels in all tissues of the body. Degradation of VLCFA takes place exclusively in peroxisomes. The enzymes that are required for the breakdown of VLCFA are functional and present inside the peroxisomes in adrenoleukodystrophy patients. Based on studies demonstrating that the expression of normal adrenoleukodystrophy protein in patient cells restored VLCFA beta-oxidation (Shinnoh et al 1995) and reduced VLCFA to normal levels (Cartier et al 1995), it has long been hypothesized that the adrenoleukodystrophy protein transports VLCFA across the peroxisomal membrane. Experiments using yeast cells and cells from adrenoleukodystrophy patients provided evidence that the adrenoleukodystrophy protein indeed transports VLCFA (as VLCFA-CoA) across the peroxisomal membrane (van Roermund et al 2008; Ofman et al 2010).
A defect in the adrenoleukodystrophy protein has two major consequences: 1) it impairs peroxisomal VLCFA beta-oxidation and 2) it raises VLCFA-CoA levels in the cytosol of the cell. These elevated levels of VLCFA-CoA in the cytosol are substrate for further elongation to even longer fatty acids by ELOVL1, the human C26-specific elongase (Ofman et al 2010; Kemp and Wanders 2010).
Origin of VLCFA
When it became clear that adrenoleukodystrophy patients have elevated levels of VLCFA, one of the first therapeutic attempts was a diet restricted in VLCFA. To limit VLCFA intake it was needed to restrict fatty foods and the outer coverings of vegetables and fruits. Administration of the VLCFA-restricted diet to seven adrenoleukodystrophy patients for 3- to 24-month periods, however, had no effect on the plasma VLCFA levels (van Duyn et al 1984).
The explanation for the ineffectiveness of this therapeutic intervention came from studies that demonstrated that only a small part of the VLCFA that accumulate in adrenoleukodystrophy is derived from the diet. The majority of the VLCFA result from endogenous synthesis through elongation of long-chain fatty acids (Tsuji et al 1981).
Over 90% of all fatty acids in the human body are long-chain fatty acids with a chain length of 16–18 carbon atoms. Fatty acids up to 16 carbon atoms in length are synthesized in the cytosol of the cell by the multifunctional protein fatty acid synthase (FAS), which utilizes acetyl-CoA, malonyl-CoA and NADPH to elongate fatty acids in two-carbon increments.
The elongation of long-chain fatty acids to VLCFA takes place at the endoplasmic membrane by four distinct enzymes; elongation of very long chain fatty acids (ELOVL), 3-ketoacyl-CoA reductase (HSD17B12), 3-hydroxyacyl dehydratase (HACD) and trans-2,3,-enoyl-CoA reductase (TECR).
The first step in this reaction is catalyzed by the enzyme referred to as “elongation of very long-chain fatty acids” (ELOVL). Seven elongases have been identified in mammals and are designated ELOVL1-7. Interestingly, only a single enzyme has been identified so far for the subsequent reaction step (Jakobsson et al 2006). This indicates that the substrate specificity (whether a saturated, monounsaturated or polyunsaturated fatty acid enters the enzyme complex) for the elongation reaction is conferred by ELOVL.
The synthesis of VLCFA (C24:0 and C26:0) requires two of the ELOVL enzymes. First the elongation complex with ELOVL6 elongates C16:0 to C20:0/C22:0 and then ELOVL1 elongates these fatty acids further to C24:0 and C26:0 (Ofman et al 2010).
The demonstration that experimental inhibition of the activity of ELOVL1 in cells derived from adrenoleukodystrophy patients leads to lower C26:0 synthesis and C26:0 levels has prompted the search for pharmacological compounds that inhibit ELOVL1 (Engelen et al 2012).
Last modified | 2019-03-13