Origin and Metabolism of VLCFA
VLCFA metabolism
Adrenoleukodystrophy is characterized by the inability of cells to metabolize/degrade VLCFA to shorter chain fatty acids. This results in elevated levels of VLCFA in all tissues of the body. The breakdown of VLCFA occurs exclusively in peroxisomes. The enzymes required to break down VLCFA are functional and present within the peroxisomes of ALD patients. Based on studies showing that expression of normal ALD protein in patient cells restores VLCFA beta-oxidation (Shinnoh et al 1995) and reduces VLCFA to normal levels (Cartier et al 1995), it has long been hypothesized that the ALD protein transports VLCFA across the peroxisomal membrane. Experiments with yeast cells and cells from ALD patients provided evidence that the ALD protein does indeed transport VLCFA (as VLCFA-CoA) across the peroxisomal membrane (van Roermund et al 2008; Ofman et al 2010).
A defect in the ALD protein has two major consequences: 1) it impairs peroxisomal VLCFA beta-oxidation and 2) it increases VLCFA-CoA levels in the cytosol of the cell. These elevated levels of cytosolic VLCFA-CoA provide a 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 ALD patients had elevated levels of VLCFA, one of the first therapeutic attempts was a VLCFA-restricted diet. To limit VLCFA intake, it was necessary to restrict fatty foods and the outer skins of vegetables and fruits. However, administration of the VLCFA-restricted diet to seven ALD patients for periods of 3 to 24 months had no effect on plasma VLCFA levels (van Duyn et al 1984).
The explanation for the ineffectiveness of this therapeutic intervention came from studies showing that only a small fraction of the VLCFA that accumulate in ALD is derived from diet. The majority of VLCFA is derived from endogenous synthesis by 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 uses acetyl-CoA, malonyl-CoA, and NADPH to elongate fatty acids in two-carbon increments.
The elongation of long-chain fatty acids to VLCFA occurs at the endoplasmic membrane by four different 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 an enzyme called “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 for the subsequent reaction step (Jakobsson et al 2006). This suggests 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 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 (Engelen et al 2012).
Last modified | 2024-06-25