Hepatic synthesis of triacylglycerols containing medium-chain fatty acids is dominated by diacylglycerol acyltransferase 1 and efficiently inhibited by etomoxir,Molecular Metabolism

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Hepatic synthesis of triacylglycerols containing medium-chain fatty acids is dominated by diacylglycerol acyltransferase 1 and efficiently inhibited by etomoxir
Molecular Metabolism ( IF 7.0 ) Pub Date : 2020-12-23 , DOI: 10.1016/j.molmet.2020.101150
Klaus Wunderling ₁ , Christina Leopold ₂ , Isabell Jamitzky ₁ , Mohamed Yaghmour ₁ , Fabian Zink ₁ , Dagmar Kratky ₃ , Christoph Thiele ₁

Affiliation

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.

中文翻译：

含有中链脂肪酸的三酰基甘油的肝脏合成由二酰基甘油酰基转移酶 1 主导，并被依托莫西有效抑制

客观的

中链脂肪酸 (MCFA) 在人类营养中发挥着越来越重要的作用。在肝脏中，一部分用于合成含有 MCFA 的甘油三酯 (MCFA-TG)，其余部分用于产生氧化能或生酮。我们研究了哪些酶催化 MCFA-TG 的合成，以及抑制 MCFA-TG 合成或脂肪酸 (FA) 氧化如何影响 MCFA 的代谢命运。

方法

FA 代谢之后是时间分辨追踪新鲜分离的小鼠肝细胞中炔标记的 FA。通过对数百种标记的脂质种类进行质谱分析，获得了定量数据。用针对 DGAT1、DGAT2 或 FA β-氧化的抑制剂处理来自二酰基甘油酰基转移酶 (DGAT)1 ^-/-小鼠的野生型肝细胞和细胞。

结果

DGAT1 的抑制或缺失导致 MCFA-TG 合成减少 70%，而长链 (LC)FA-TG 合成减少 20%。相比之下，DGAT2 抑制使 MCFA-TG 形成增加了 50%，而 LCFA-TG 合成减少了 5-25%。特异性抑制剂teglicar对β-氧化的抑制显着增加了MCFA-TG的合成。相反，广泛使用的β-氧化抑制剂依托莫西阻断了 MCFA-TG 的合成，表现出 DGAT1 抑制作用。