Lipid droplets (LDs) are cellular organelles critical for lipid homeostasis, with intramyocyte LD accumulation implicated in metabolic disorder-associated heart diseases. Here we identify a human long non-coding RNA, Lipid-Droplet Transporter (LIPTER), essential for LD transport in human cardiomyocytes. LIPTER binds phosphatidic acid and phosphatidylinositol 4-phosphate on LD surface membranes and the MYH10 protein, connecting LDs to the MYH10-ACTIN cytoskeleton and facilitating LD transport. LIPTER and MYH10 deficiencies impair LD trafficking, mitochondrial function and survival of human induced pluripotent stem cell-derived cardiomyocytes. Conditional Myh10 deletion in mouse cardiomyocytes leads to LD accumulation, reduced fatty acid oxidation and compromised cardiac function. We identify NKX2.5 as the primary regulator of cardiomyocyte-specific LIPTER transcription. Notably, LIPTER transgenic expression mitigates cardiac lipotoxicity, preserves cardiac function and alleviates cardiomyopathies in high-fat-diet-fed and Lepr^db/db mice. Our findings unveil a molecular connector role of LIPTER in intramyocyte LD transport, crucial for lipid metabolism of the human heart, and hold significant clinical implications for treating metabolic syndrome-associated heart diseases.

脂滴 (LD) 是对脂质稳态至关重要的细胞器，肌细胞内 LD 的积累与代谢紊乱相关的心脏病有关。在这里，我们鉴定了一种人类长链非编码 RNA，即脂滴转运蛋白 ( LIPTER )，它对于人类心肌细胞中的 LD 转运至关重要。LIPTER结合 LD 表面膜和 MYH10 蛋白上的磷脂酸和磷脂酰肌醇 4-磷酸，将 LD 连接到 MYH10-ACTIN 细胞骨架并促进 LD 转运。LIPTER和MYH10缺陷会损害 LD 运输、线粒体功能和人类诱导多能干细胞来源的心肌细胞的存活。小鼠心肌细胞中条件性Myh10缺失会导致 LD 积累、脂肪酸氧化减少和心脏功能受损。我们确定NKX2.5是心肌细胞特异性LIPTER转录的主要调节因子。值得注意的是，LIPTER转基因表达可减轻高脂饮食小鼠和Lepr ^db/db小鼠的心脏脂毒性，保留心脏功能并减轻心肌病。我们的研究结果揭示了LIPTER在肌细胞内 LD 转运中的分子连接器作用，这对人类心脏的脂质代谢至关重要，并对治疗代谢综合征相关心脏病具有重要的临床意义。