Department of Pharmacology,School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, P.R. China.
Cardiovascular Research Center, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, P.R. China.
Cell Cycle. 2021 Sep;20(18):1890-1906. doi: 10.1080/15384101.2021.1965734. Epub 2021 Aug 23.
Lipid droplets (LDs), which are neutral lipid storage organelles, are important for lipid metabolism and energy homeostasis. LD lipolysis and interactions with mitochondria are tightly coupled to cellular metabolism and may be potential targets to buffer the effects of excessive toxic lipid species levels. Acetylcholine (ACh), the major neurotransmitter of the vagus nerve, exhibits cardioprotective effects. However, limited research has focused on its effects on LD lipolysis and the LD-mitochondria association in fatty acid (FA) overload models. Here, we reveal that palmitate (PA) induces an increase in expression of the FA transport protein cluster of differentiation 36 (CD36) and LD formation; remarkably reduces the expression of lipases involved in triacylglycerol (TAG) lipolysis, such as adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL) and monoacylglycerol lipase (MGL); impairs LD-mitochondria interaction; and decreases perilipin 5 (PLIN5) expression, resulting in LD accumulation and mitochondrial dysfunction, which ultimately lead to cardiomyocyte apoptosis. ACh significantly upregulates PLIN5 expression and improved LD lipolysis and the LD-mitochondria association. Moreover, ACh reduces CD36 expression, LD deposition and mitochondrial dysfunction, ultimately suppressing apoptosis in PA-treated neonatal rat ventricular cardiomyocytes (NRVCs). Knockdown of PLIN5, which plays a role in LD-mitochondria contact site formation, abolishes the protective effects of ACh in PA-treated NRVCs. Thus, ACh protects cardiomyocytes from PA-induced apoptosis, at least partly, by promoting LD lipolysis and activating LD-mitochondria interactions via PLIN5. These findings may aid in developing novel therapeutic approaches that target LD lipolysis and PLIN5-mediated LD-mitochondria interactions to prevent or alleviate lipotoxic cardiomyopathy.
脂滴（LDs）是中性脂质储存细胞器，对于脂质代谢和能量稳态至关重要。LD 的脂解作用和与线粒体的相互作用与细胞代谢紧密偶联，可能是缓冲过量毒性脂质水平影响的潜在靶点。乙酰胆碱（ACh）是迷走神经的主要神经递质，具有心脏保护作用。然而，关于 ACh 对脂肪酸（FA）过载模型中 LD 脂解作用和 LD-线粒体关联的影响，研究有限。在这里，我们揭示了软脂酸（PA）诱导 FA 转运蛋白 CD36 表达增加和 LD 形成；显著降低了参与三酰基甘油（TAG）脂解的脂肪酶的表达，如脂肪甘油三酯脂肪酶（ATGL）、激素敏感脂肪酶（HSL）和单酰基甘油脂肪酶（MGL）；损害 LD-线粒体相互作用；并降低 perilipin 5（PLIN5）的表达，导致 LD 积累和线粒体功能障碍，最终导致心肌细胞凋亡。ACh 显著上调 PLIN5 的表达，改善 LD 脂解作用和 LD-线粒体关联。此外，ACh 降低 CD36 表达、LD 沉积和线粒体功能障碍，最终抑制 PA 处理的新生大鼠心室心肌细胞（NRVCs）中的凋亡。PLIN5 在 LD-线粒体接触位点形成中发挥作用，其敲低消除了 ACh 在 PA 处理的 NRVCs 中的保护作用。因此，ACh 通过促进 LD 脂解作用和激活 LD-线粒体相互作用来保护心肌细胞免受 PA 诱导的凋亡，至少部分是通过 PLIN5 实现的。这些发现可能有助于开发新的治疗方法，通过靶向 LD 脂解作用和 PLIN5 介导的 LD-线粒体相互作用来预防或减轻脂肪毒性心肌病。
