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.