Enhancing Cardiac Triacylglycerol Metabolism Improves Recovery From Ischemic Stress.
Enhancing Cardiac Triacylglycerol Metabolism Improves Recovery From Ischemic Stress.
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作者：
Kolwicz SC Jr;Liu L;Goldberg IJ;Tian R
心脏三酰甘油（TAG）含量升高传统上等同于心脏脂肪毒性，并被认为是心脏功能障碍的罪魁祸首。然而，之前的研究表明，肌球蛋白重链介导的二酰甘油转移酶 1 (MHC-DGAT1)（TAG 合成的主要酶）心脏特异性过度表达，尽管保持了高 TAG 含量，但在两种脂毒性小鼠模型中保留了心脏功能。因此，我们研究了在常氧和缺血再灌注条件下，DGAT1 过表达导致的心肌细胞 TAG 水平增加是否会导致心脏 TAG 周转率的变化。 MHC-DGAT1 小鼠的 TAG 含量和合成率升高，但不会改变心脏功能、底物氧化或心肌能量。 MHC-DGAT1心脏发生缺血诱导的脂肪分解；然而，当提供长链脂肪酸的生理混合物时，TAG周转率的提高与低流量缺血的功能恢复改善相关。相反，再灌注期间棕榈酸酯的外源供应抑制了 TAG 周转率的升高，并损害了 MHC-DGAT1 心脏的缺血恢复。总的来说，这项研究表明，TAG 含量升高，伴随着周转率的提高，不会对心脏功能产生不利影响，事实上，可以保护心脏免受缺血性应激。此外，结果强调了在评估心脏脂质代谢及其与心脏功能的关系时外源性供应脂肪酸的重要性。
Elevated cardiac triacylglycerol (TAG) content is traditionally equated with cardiolipotoxicity and suggested to be a culprit in cardiac dysfunction. However, previous work demonstrated that myosin heavy-chain–mediated cardiac-specific overexpression of diacylglycerol transferase 1 (MHC-DGAT1), the primary enzyme for TAG synthesis, preserved cardiac function in two lipotoxic mouse models despite maintaining high TAG content. Therefore, we examined whether increased cardiomyocyte TAG levels due to DGAT1 overexpression led to changes in cardiac TAG turnover rates under normoxia and ischemia-reperfusion conditions. MHC-DGAT1 mice had elevated TAG content and synthesis rates, which did not alter cardiac function, substrate oxidation, or myocardial energetics. MHC-DGAT1 hearts had ischemia-induced lipolysis; however, when a physiologic mixture of long-chain fatty acids was provided, enhanced TAG turnover rates were associated with improved functional recovery from low-flow ischemia. Conversely, exogenous supply of palmitate during reperfusion suppressed elevated TAG turnover rates and impaired recovery from ischemia in MHC-DGAT1 hearts. Collectively, this study shows that elevated TAG content, accompanied by enhanced turnover, does not adversely affect cardiac function and, in fact, provides cardioprotection from ischemic stress. In addition, the results highlight the importance of exogenous supply of fatty acids when assessing cardiac lipid metabolism and its relationship with cardiac function.