Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA, 98109, USA.
Sci Rep. 2018 Mar 21;8(1):4983. doi: 10.1038/s41598-018-23223-7.
It is increasingly recognized that synthesis and turnover of cardiac triglyceride (TG) play a pivotal role in the regulation of lipid metabolism and function of the heart. The last step in TG synthesis is catalyzed by diacylglycerol:acyltransferase (DGAT) which esterifies the diacylglycerol with a fatty acid. Mammalian heart has two DGAT isoforms, DGAT1 and DGAT2, yet their roles in cardiac metabolism and function remain poorly defined. Here, we show that inactivation of DGAT1 or DGAT2 in adult mouse heart results in a moderate suppression of TG synthesis and turnover. Partial inhibition of DGAT activity increases cardiac fatty acid oxidation without affecting PPARα signaling, myocardial energetics or contractile function. Moreover, coinhibition of DGAT1/2 in the heart abrogates TG turnover and protects the heart against high fat diet-induced lipid accumulation with no adverse effects on basal or dobutamine-stimulated cardiac function. Thus, the two DGAT isoforms in the heart have partially redundant function, and pharmacological inhibition of one DGAT isoform is well tolerated in adult hearts.
人们越来越认识到，心脏甘油三酯 (TG) 的合成和周转在调节脂质代谢和心脏功能方面起着关键作用。TG 合成的最后一步是由二酰基甘油：酰基转移酶 (DGAT) 催化的，该酶将二酰基甘油与脂肪酸酯化。哺乳动物心脏有两种 DGAT 同工酶，即 DGAT1 和 DGAT2，但它们在心脏代谢和功能中的作用仍未明确。在这里，我们发现成年小鼠心脏中 DGAT1 或 DGAT2 的失活导致 TG 合成和周转的适度抑制。DGAT 活性的部分抑制增加了心脏脂肪酸氧化，而不影响 PPARα 信号、心肌能量或收缩功能。此外，心脏中 DGAT1/2 的双重抑制可消除 TG 周转，并防止高脂肪饮食引起的脂质积累，对基础或多巴酚丁胺刺激的心脏功能没有不良影响。因此，心脏中的两种 DGAT 同工酶具有部分冗余功能，并且在成年心脏中抑制一种 DGAT 同工酶的药理学作用具有良好的耐受性。
