Hepatic synthesis of triacylglycerols containing medium-chain fatty acids is dominated by diacylglycerol acyltransferase 1 and efficiently inhibited by etomoxir
| Autor: | Fabian Zink, Isabell Jamitzky, Klaus Wunderling, Dagmar Kratky, Christina Leopold, Mohamed H. Yaghmour, Christoph Thiele |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Male
0301 basic medicine lcsh:Internal medicine Teglicar 030209 endocrinology & metabolism Oxidative phosphorylation Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Ketogenesis Animals Diacylglycerol O-Acyltransferase Etomoxir lcsh:RC31-1245 Metabolic tracing Molecular Biology Triglycerides Mice Knockout chemistry.chemical_classification Lipogenesis Fatty Acids Fatty acid Cell Biology Metabolism MCFA Lipid Metabolism Mice Inbred C57BL 030104 developmental biology Human nutrition Enzyme Liver Biochemistry chemistry Hepatocytes Epoxy Compounds Original Article Diacylglycerol Acyltransferase Oxidation-Reduction |
| Zdroj: | Molecular Metabolism Molecular Metabolism, Vol 45, Iss, Pp 101150-(2021) |
| ISSN: | 2212-8778 |
| Popis: | Objective 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. Methods 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. Results 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. Conclusions 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. Graphical abstract Medium-chain fatty acids (red) are oxidized or incorporated into triglycerides by DGAT1 in the liver. The popular experimental drug etomoxir inhibits the oxidation and, unexpectedly, blocks triglyceride formation by DGAT1.Image 1 |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|