ECHDC1 knockout mice accumulate ethyl-branched lipids and excrete abnormal intermediates of branched-chain fatty acid metabolism
| Autor: | Younes Achouri, Joseph P. Dewulf, Emile Van Schaftingen, Stéphanie Paquay, Etienne Marbaix, Guido T. Bommer |
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| Přispěvatelé: | UCL - SSS/DDUV/BCHM - Biochimie-Recherche métabolique |
| Rok vydání: | 2021 |
| Předmět: |
ethyl-branched fatty acids
acyltaurine mm-CoA methylmalonyl-CoA Carboxy-Lyases ECHDC1 enzyme ethylmalonyl-CoA decarboxylase FASN fatty acid synthase ACC acetyl-CoA carboxylase 2-dimethylmalonyl-CoA Biochemistry em-CoA ethylmalonyl-CoA Excretion chemistry.chemical_compound Mice SIM selected-ion monitoring Methylmalonyl-CoA In vivo ECHDC1 plasmanylcholine Animals CDI carbonyldiimidazole Molecular Biology chemistry.chemical_classification Mice Knockout 2 2-dimethylmalonic acid ethylmalonyl-CoA 2 2-dimethylmalonyl-CoA ethylmalonic acid methyl-branched fatty acids Fatty Acids FA fatty acid branched-chain FAs Cell Biology Metabolism Pyruvate carboxylase BAT brown adipose tissue Cytosol Enzyme acylglycine chemistry Knockout mouse 2-dimethylmalonic acid Acyl Coenzyme A Research Article |
| Zdroj: | The Journal of Biological Chemistry The Journal of biological chemistry, Vol. 297, no.4, p. 101083 (2021) |
| ISSN: | 1083-351X |
| Popis: | The cytosolic enzyme ethylmalonyl-CoA decarboxylase (ECHDC1) decarboxylates ethyl- or methyl-malonyl-CoA, two side-products of acetyl-CoA carboxylase. These CoA derivatives can be used to synthesize a subset of branched-chain fatty acids (FAs). We previously found that ECHDC1 limits the synthesis of these abnormal FAs in cell lines, but its effects in vivo are unknown. To further evaluate the effects of ECHDC1 deficiency, we generated knock-out mice. These mice were viable, fertile, showed normal postnatal growth, and lacked obvious macroscopic and histologic changes. Surprisingly, tissues from wild-type mice already contained methyl-branched FAs due to methylmalonyl-CoA incorporation, but these FAs were only increased in the intraorbital glands of ECHDC1 knock-out mice. In contrast, ECHDC1 knock-out mice accumulated 16- to 20-carbon FAs carrying ethyl-branches in all tissues, which were undetectable in wild-type mice. Ethyl-branched FAs were incorporated into different lipids, including acylcarnitines, phosphatidylcholines, plasmanylcholines, and triglycerides. Interestingly, we found a variety of unusual glycine-conjugates in the urine of knock-out mice, which included adducts of ethyl-branched compounds in different stages of oxidation. This suggests that the excretion of potentially toxic intermediates of branched-chain FA metabolism might prevent a more dramatic phenotype in these mice. Curiously, ECHDC1 knock-out mice also accumulated 2,2-dimethylmalonyl-CoA. This indicates that the broad specificity of ECHDC1 might help eliminate a variety of potentially dangerous branched-chain dicarboxylyl-CoAs. We conclude that ECHDC1 prevents the formation of ethyl-branched FAs, and that urinary excretion of glycine-conjugates allows mice to eliminate potentially deleterious intermediates of branched-chain FA metabolism. |
| Databáze: | OpenAIRE |
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