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Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Wunderling, K; Leopold, C; Jamitzky, I; Yaghmour, M; Zink, F; Kratky, D; Thiele, C.
Hepatic synthesis of triacylglycerols containing medium-chain fatty acids is dominated by diacylglycerol acyltransferase 1 and efficiently inhibited by etomoxir.
Mol Metab. 2020; 45: 101150-101150.
Doi: 10.1016/j.molmet.2020.101150
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- Co-Autor*innen der Med Uni Graz
- Kratky Dagmar
- Leopold Christina
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- Abstract:
- Medium-chain fatty acids (MCFAs) play an increasing role in human nutrition. In the liver, one fraction is used for synthesis of MCFA-containing triacylglycerol (MCFA-TG), and the rest is used for oxidative energy production or ketogenesis. We investigated which enzymes catalyse the synthesis of MCFA-TG and how inhibition of MCFA-TG synthesis or fatty acid (FA) oxidation influences the metabolic fate of the MCFAs. FA metabolism was followed by time-resolved tracing of alkyne-labelled FAs in freshly isolated mouse hepatocytes. Quantitative data were obtained by mass spectrometry of several hundred labelled lipid species. Wild-type hepatocytes and cells from diacylglycerol acyltransferase (DGAT)1-/- mice were treated with inhibitors against DGAT1, DGAT2, or FA β-oxidation. Inhibition or deletion of DGAT1 resulted in a reduction of MCFA-TG synthesis by 70%, while long-chain (LC)FA-TG synthesis was reduced by 20%. In contrast, DGAT2 inhibition increased MCFA-TG formation by 50%, while LCFA-TG synthesis was reduced by 5-25%. Inhibition of β-oxidation by the specific inhibitor teglicar strongly increased MCFA-TG synthesis. In contrast, the widely used β-oxidation inhibitor etomoxir blocked MCFA-TG synthesis, phenocopying DGAT1 inhibition. DGAT1 is the major enzyme for hepatic MCFA-TG synthesis. Its loss can only partially be compensated by DGAT2. Specific inhibition of β-oxidation leads to a compensatory increase in MCFA-TG synthesis, whereas etomoxir blocks both β-oxidation and MCFA-TG synthesis, indicating a strong off-target effect on DGAT1. Copyright © 2020 The Author(s). Published by Elsevier GmbH.. All rights reserved.
- Find related publications in this database (Keywords)
- MCFA
- Metabolic tracing
- Etomoxir
- Teglicar