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脂滴相关长链非编码 RNA LIPTER 可维持心脏脂质代谢。

Lipid droplet-associated lncRNA LIPTER preserves cardiac lipid metabolism.

机构信息

Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA.

Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.

出版信息

Nat Cell Biol. 2023 Jul;25(7):1033-1046. doi: 10.1038/s41556-023-01162-4. Epub 2023 Jun 1.

DOI:10.1038/s41556-023-01162-4
PMID:37264180
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10344779/
Abstract

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 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.

摘要

脂滴 (LDs) 是维持脂质稳态的关键细胞细胞器，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非编码 RNA，即脂滴转运蛋白 (LIPTER)，它对于人心肌细胞中 LD 的转运是必不可少的。LIPTER 结合 LD 表面膜上的磷酸脂酸和磷脂酰肌醇 4-磷酸以及 MYH10 蛋白，将 LD 与 MYH10-肌动蛋白细胞骨架连接起来，并促进 LD 的转运。LIPTER 和 MYH10 的缺乏会损害 LD 的运输、线粒体功能以及人诱导多能干细胞衍生的心肌细胞的存活。在小鼠心肌细胞中条件性敲除 Myh10 会导致 LD 积累、脂肪酸氧化减少以及心脏功能受损。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 的转基因表达减轻了心脏的脂毒性，维持了心脏功能，并缓解了高脂肪饮食喂养和 Lepr 小鼠的心肌病。我们的研究结果揭示了 LIPTER 在肌细胞内 LD 转运中的分子连接作用，对人类心脏的脂质代谢至关重要，并为治疗与代谢综合征相关的心脏病提供了重要的临床意义。

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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9087/10344779/6c201c5a2c56/41556_2023_1162_Fig9_ESM.jpg
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