Lipid overload-induced RTN3 activation leads to cardiac dysfunction by promoting lipid droplet biogenesis.

Lipid droplet (LD) accumulation is a notable feature of obesity-induced cardiomyopathy, while underlying mechanism remains poorly understood. Here we show that mice fed with high-fat diet (HFD) exhibited significantly increase in cardiac LD and RTN3 expression, accompanied by cardiac function impairment. Multiple loss- and gain-of function experiments indicate that RTN3 is critical to HFD-induced cardiac LD accumulation. Mechanistically, RTN3 directly bonds with fatty acid binding protein 5 (FABP5) to facilitate the directed transport of fatty acids to endoplasmic reticulum, thereby promoting LD biogenesis in a diacylglycerol acyltransferase 2 dependent way. Moreover, lipid overload-induced RTN3 upregulation is due to increased expression of CCAAT/enhancer binding protein α (C/EBPα), which positively regulates RTN3 transcription by binding to its promoter region. Notably, above findings were verified in the myocardium of obese patients. Our findings suggest that manipulating LD biogenesis by modulating RTN3 may be a potential strategy for treating cardiac dysfunction in obese patients.