Abstract 14068: The Lipid Droplet-Associated lncRNA LIPTER Preserves Cardiac Lipid Metabolism of Human Cardiomyocytes

Abstract

Background: Lipid droplets (LDs) are cellular organelles critical for maintaining lipid homeostasis. LD accumulation is associated with cardiomyopathies and heart failure in hyperlipidemia-related metabolic disorders. Currently, the cardiomyocyte (CM) intrinsic mechanism governing LD transport remains poorly understood. Hypothesis: We hypothesize that long non-coding RNA (lncRNA) can directly participate in LD transport in human CMs. Goals: To reveal a lncRNA LIPTER -mediated lipid droplet transport system in human CMs and define its role in preserving cardiac lipid metabolism. Methods: LIPTER and MYH10 were knocked out in human iPS cells using CRISPR/Cas-9. Myh10 was conditionally knocked out in mouse CMs. A LIPTER transgenic mouse line was established to test the effects of LIPTER transgene on high fat diet-induced cardiac dysfunction. LIPTER was delivered into CMs of Lepr db/db mice using AAV-9. Results: We identified a human lncRNA, Lipid-Droplet Transporter (LIPTER), essential for LD transport in human CMs. 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 iPS cell-derived CMs. Conditional Myh10 deletion in mouse CMs leads to LD accumulation, reduced fatty acid oxidation, and compromised cardiac function. We identify NKX2.5 as the primary regulator of CM-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. Conclusions: We 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.