Department of Pharmacology, School of Medicine, Ewha Womans University, Seoul, Republic of Korea.
Department of Internal Medicine, School of Medicine, Ewha Womans University, Seoul, Republic of Korea.
Cardiovasc Res. 2017 Aug 1;113(10):1137-1147. doi: 10.1093/cvr/cvx064.
Autophagy is essential to maintain tissue homeostasis, particularly in long-lived cells such as cardiomyocytes. Whereas many studies support the importance of autophagy in the mechanisms underlying obesity-related cardiac dysfunction, the role of autophagy in cardiac lipid metabolism remains unclear. In the heart, lipotoxicity is exacerbated by cardiac lipoprotein lipase (LPL), which mediates accumulation of fatty acids to the heart through intravascular triglyceride (TG) hydrolysis.
In both genetic and dietary models of obesity, we observed a substantial increase in cardiac LPL protein levels without any change in messenger ribonucleic acid (mRNA). This was accompanied by a dramatic down-regulation of autophagy in the heart, as revealed by reduced levels of unc-51 like kinase-1 (ULK1) protein. To further explore the relationship between cardiac LPL and autophagy, we generated cardiomyocyte-specific knockout mice for ulk1 (Myh6-cre/ulk1fl/fl), Lpl (Myh6-cre/Lplfl/fl), and mice with a combined deficiency (Myh6-cre/ulk1fl/flLplfl/fl). Similar to genetic and dietary models of obesity, Myh6-cre/ulk1fl/fl mice had a substantial increase in cardiac LPL levels. When these mice were fed a high-fat diet (HFD), they showed elevated cardiac TG levels and deterioration in heart function. However, with combined deletion of LPL and ULK1 in Myh6-cre/ulk1fl/flLplfl/fl mice, HFD feeding did not lead to alterations in levels of TG or diacylglycerol, or in cardiac function. To further elucidate the role of autophagy in cardiac lipid metabolism, we infused a peptide that enhanced autophagy (D-Tat-beclin1). This effectively lowered LPL levels at the coronary lumen by restoring autophagy in the genetic model of obesity. This decrease in cardiac luminal LPL was associated with a reduction in TG levels and recovery of cardiac function.
These results provide clear evidence of the critical role of modulating cardiac LPL activity through autophagy-mediated proteolytic clearance as a potential novel strategy to overcome obesity-related cardiomyopathy.
自噬对于维持组织内稳态至关重要，尤其是在心肌细胞等寿命较长的细胞中。虽然许多研究支持自噬在肥胖相关心功能障碍的机制中很重要，但自噬在心脏脂质代谢中的作用仍不清楚。在心脏中，脂毒性会被心脏脂蛋白脂肪酶（LPL）加剧，该酶通过血管内甘油三酯（TG）水解将脂肪酸介导到心脏。
在肥胖的遗传和饮食模型中，我们观察到心脏 LPL 蛋白水平显著增加，而信使核糖核酸（mRNA）没有任何变化。这伴随着心脏自噬的急剧下调，表现为 UNC-51 样激酶-1（ULK1）蛋白水平降低。为了进一步探讨心脏 LPL 和自噬之间的关系，我们生成了肌球蛋白重链 6 启动子（Myh6-cre）驱动的肌球蛋白轻链 1 缺失（ulk1fl/fl）、LPL 缺失（Lplfl/fl）和 ULK1 和 LPL 双缺失（Myh6-cre/ulk1fl/flLplfl/fl）的心肌细胞特异性敲除小鼠。与肥胖的遗传和饮食模型相似，Myh6-cre/ulk1fl/fl 小鼠的心脏 LPL 水平显著增加。当这些小鼠喂食高脂肪饮食（HFD）时，它们表现出心脏 TG 水平升高和心功能恶化。然而，在 Myh6-cre/ulk1fl/flLplfl/fl 小鼠中同时缺失 LPL 和 ULK1 时，HFD 喂养不会导致 TG 或二酰基甘油水平或心脏功能的改变。为了进一步阐明自噬在心脏脂质代谢中的作用，我们输注了一种增强自噬的肽（D-Tat-beclin1）。这通过在肥胖的遗传模型中恢复自噬，有效地降低了冠状动脉腔内的 LPL 水平。心脏腔内 LPL 的减少与 TG 水平的降低和心脏功能的恢复有关。
这些结果提供了明确的证据，表明通过自噬介导的蛋白水解清除来调节心脏 LPL 活性是克服肥胖相关心肌病的一种潜在新策略。
