The role of acetyl-L-carnitine on the long chain fatty acid metabolism in MPTP-treated rats
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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.
- Health Sciences