Glucolipotoxicity following nutrient-overload causes cardiomyocyte injury by inhibiting TFEB and suppressing lysosomal function. We ascertained if besides the amount, do the type of fatty acid (FA) and duration of FA exposure regulate TFEB action and dictate cardiomyocyte viability. Saturated FA, palmitate, but not polyunsaturated FAs decreased TFEB content in a concentration- and time-dependent manner in cardiomyocytes. Hearts from high-fat high-sucrose diet-fed mice exhibited a temporal decline in nuclear TFEB content with marked elevation of diacylglycerol and triacylglycerol, suggesting that lipid deposition and TFEB loss are concomitant molecular events. Next, we examined the identity of signaling and metabolic pathways engaged by the loss of TFEB action in the cardiomyocyte. Transcriptome analysis in murine cardiomyocytes with targeted deletion of myocyte TFEB (TFEB^−/−) revealed enrichment of differentially expressed genes (DEG) representing pathways of nutrient metabolism, DNA damage and repair, cell death and cardiac function. Strikingly, genes involved in macroautophagy, mitophagy and lysosome function constituted a small portion of DEGs in TFEB^−/− cardiomyocytes. In myoblasts and/or myocytes, nutrient overload-induced lipid droplet accumulation and caspase-3 activation were exacerbated by silencing TFEB or attenuated by overexpressing constitutively active TFEB. The effect of TFEB overexpression were persistent in the presence of Atg7 loss of function, signifying that the effect of TFEB in the myocyte is independent of changes in the macroautophagy pathway. In the cardiomyocyte, the non-canonical effect of TFEB to reprogram energy metabolism is more evident than the canonical action of TFEB on lysosomal autophagy. Loss of TFEB function perturbs metabolic pathways in the cardiomyocyte and renders the heart prematurely susceptible to nutrient overload-induced injury.

营养素超负荷后的糖脂毒性通过抑制TFEB和抑制溶酶体功能而引起心肌细胞损伤。我们确定了脂肪酸（FA）的类型和FA暴露时间是否能调节TFEB的作用并决定心肌细胞的活力。心肌中饱和脂肪酸，棕榈酸酯而不是多不饱和脂肪酸以浓度和时间依赖性方式降低TFEB含量。高脂高蔗糖饮食喂养小鼠的心脏显示出核TFEB含量随时间下降，二酰基甘油和三酰基甘油明显升高，表明脂质沉积和TFEB丢失是伴随的分子事件。接下来，我们检查了心肌细胞中TFEB作用丧失参与的信号传导和代谢途径的身份。^-/-）揭示了差异表达基因（DEG）的富集，代表了营养物质代谢，DNA损伤和修复，细胞死亡和心脏功能的途径。令人惊讶的是，参与巨自噬，线粒体和溶酶体功能的基因在TFEB ^-/-中仅占DEG的一小部分。心肌细胞。在成肌细胞和/或心肌细胞中，沉默TFEB会加剧养分过载诱导的脂质滴积聚和caspase-3激活，而过表达组成型活性TFEB会减弱养分过载。在存在Atg7功能丧失的情况下，TFEB过表达的作用持续存在，这表明TFEB在肌细胞中的作用与巨噬细胞自噬途径的变化无关。在心肌细胞中，TFEB重新编程能量代谢的非经典作用比TFEB对溶酶体自噬的经典作用更为明显。TFEB功能的丧失会扰乱心肌细胞的代谢途径，并使心脏过早易受营养素超负荷引起的损伤。