ECHDC1 prevents the synthesis of branched fatty acids
(2019) Keystone symposium: Lipidomics and functional metabolic pathways in disease — Location: Steamboat Springs, Colorado, U.S.A. (1.April.2019)
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- Abstract
- Fatty acid synthesis proceeds by the consecutive addition of two-carbon units from malonyl-CoA to acetyl-CoA. This leads to linear structures. Yet, in rare cases fatty acids can contain branches. Most commonly, methyl-branches occur on the extremity of the carbon chain, when breakdown products of branched amino acids are used to start fatty acid synthesis. ECHDC1 can decarboxylate (m)ethyl-malonyl-CoA. We hypothesized that the inactivation of ECHDC1 would lead to the formation of fatty acids with (m)ethyl- branches in the middle of the carbon chain, when fatty acid synthase erroneously uses methyl- or ethyl-malonyl-CoA instead of malonyl-CoA to extend the carbon chain. To test this hypothesis, we genetically inactivated ECHDC1 in cell lines and in mice. We discovered accumulation of methyl-branched fatty acids in two different ECHDC1-deficient adipocyte cell models and in different tissues of ECHDC1 knockout mice. No ethyl-branched fatty acids were detected in these samples, although ethyl-malonyl-CoA concentrations were strongly increased. Surprisingly, ECHDC1 knockout mice excreted short ethyl-branched fatty acids and their -keto, -hydroxy or monounsaturated equivalents as glycine or taurine conjugates in urine. Preliminary evidence suggests that these adducts are abortive intermediates of mitochondrial fatty acid synthesis. Thus, our studies demonstrate that the enzyme ECHDC1 serves to prevent the formation of branched-chain fatty acids in both cytoplasm and mitochondria.
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Dewulf, J., & et al. (2019). ECHDC1 prevents the synthesis of branched fatty acids. Keystone symposium: Lipidomics and functional metabolic pathways in disease, Steamboat Springs, Colorado, U.S.A. https://hdl.handle.net/2078.5/170538