Summary: | Very long-chain fatty acids, especially n-3 polyunsaturated fatty acids (PUFAs), play an
integral role in several physiological processes and are essential components of
phospholipids in membranes. Fatty acid elongation in the cytoplasm (endoplasmic
reticulum) and in the peroxisomes utilizes malonyl-CoA as a carbon source, whereas
mitochondria1 elongation uses acetylcarnitine or acetyl-CoA. Fatty acids are involved in
the biosynthesis of docosahexaenoic acid (DHA, 22:6n-3) and the formation of
acetylcarnitine. DHA's last biosynthesis step consists of one peroxisomal P-oxidation
cycle of its precursor, C24:6n-3. After a few cycles of peroxisomal P-oxidation, the fatty
acid is transported into the mitochondrion for further P-oxidation.
Previous research showed that MPTP causes a decrease of acetyl-CoA production due to
the inhibition of the acyl-CoA dehydrogenase enzymes, ETF, or ETF-QO. Experimental
animals treated with MPTP developed neurological damage which leads to clinical
symptoms similar to Parkinson's disease and a metabolic profile similar to GA II,
suggesting that it may be possible to induce a deficiency similar to GA II. GA II may in
several ways be linked to extrapyramidal symptoms, such as a decrease of acetyl-CoA
production which is characteristic of GA II. We argued that if the neurological
symptoms are the result of deceased acetyl-CoA production, which could prevent fatty
acid elongation, the problem could possibly be rectified by supplementation with
acetylcarnitine. Acetylcarnitine supplementation had already been shown to prevent the
development of the clinical symptoms associated with MPTP treatment, but it has not
been known if acetylcarnitine will increase the fatty acid elongation.
Our first objective of this study was to determine whether ALCAR plays a role in very
long-chain fatty acid metabolism by influencing the fatty acid elongation process. To test
this hypothesis, rats were treated with ALCAR and their serum analysed for certain
metabolites. The fatty acid concentrations were expressed in consequential ratios
(C24:C22 and C26:C22), which provide a more sensitive criterion than concentrations
per se to indicate the possible defective enzymes involved in the fatty acid elongation
pathway. The results showed that ALCAR had no prominent role in long-chain fatty acid
metabolism and could therefore not be responsible for the preservation of peroxisomal
P-oxidation or fatty acid elongation. However, concentrations of the C22:0 and C24:0
fatty acids were increased on certain days. A statistical significant higher concentration
in the experimental group was observed in the C22:0concentrations on day 1, 7 and 13
and for the C24:0 concentrations on day 7, 13 and 14.
Our second objective was to determine acetyl- and acylcamitine concentrations in
ALCAR treated rats before and after a single treatment with the GA II inducing chemical,
MPTP. The acetylcarnitine concentration of the experimental group was statistically
significant elevated on day 1, but thereafter the concentrations of both groups stabilized
and were similar. The glutarylcarnitine concentrations of the experimental group
significantly increased after MPTP treatment.
Our data suggest that the influence of ALCAR on VLCFA metabolism is not significant
enough to substantiate the hypothesis that ALCAR plays an appreciable role in
preserving peroxisomal P-oxidation and fatty acid elongation. ALCAR does not
influence the VLCFA biosynthesis under normal circumstances, but it does activate
VLCFA biosynthesis when their concentrations are decreased. ALCAR treatment can
however be considered as safe in the treatment of VLCFA and neurodegenerative defects,
since it has little/no effect on the VLCFA biosynthesis. ALCAR promoted the formation
of some acylcamitines (especially glutarylcamitine), conjugates of the GA II metabolites,
after MPTP treatment. Thus, it can be concluded that ALCAR possibly play an important
role in the detoxification of GA II metabolites. === Thesis (M.Sc. (Pharmaceutical Chemistry))--North-West University, Potchefstroom Campus, 2006.
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