Division of Cardiology, Departments of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China; Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, 430030, PR China.
Division of Cardiology, Departments of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China; Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, 430030, PR China; Genetic Diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China.
Mol Metab. 2024 Oct;88:102011. doi: 10.1016/j.molmet.2024.102011. Epub 2024 Aug 20.
Emerging evidence highlights the pivotal roles of long non-coding RNAs (lncRNAs) in lipid metabolism. Apoprotein C3 (ApoC3) is a well-established therapeutic target for hypertriglyceridemia and exhibits a strong association with cardiovascular disease. However, the exact mechanisms via which the lncRNAs control ApoC3 expression remain unclear.
We identified a novel long noncoding RNA (lncRNA), GM47544, within the ApoA1/C3/A4/A5 gene cluster. Subsequently, the effect of GM47544 on intracellular triglyceride metabolism was analyzed. The diet-induced mouse models of hyperlipidemia and atherosclerosis were established to explore the effect of GM47544 on dyslipidemia and plaque formation in vivo. The molecular mechanism was explored through RNA sequencing, immunoprecipitation, RNA pull-down assay, and RNA immunoprecipitation.
GM47544 was overexpressed under high-fat stimulation. GM47544 effectively improved hepatic steatosis, reduced blood lipid levels, and alleviated atherosclerosis in vitro and in vivo. Mechanistically, GM47544 directly bound to ApoC3 and facilitated the ubiquitination at lysine 79 in ApoC3, thereby facilitating ApoC3 degradation via the ubiquitin-proteasome pathway. Moreover, we identified AP006216.5 as the human GM47544 transcript, which fulfills a comparable function in human hepatocytes.
The identification of GM47544 as a lncRNA modulator of ApoC3 reveals a novel mechanism of post-translational modification, with significant clinical implications for the treatment of hypertriglyceridemia and atherosclerosis.
新出现的证据强调了长非编码 RNA（lncRNA）在脂质代谢中的关键作用。载脂蛋白 C3（ApoC3）是治疗高甘油三酯血症的一个明确的治疗靶点，并且与心血管疾病有很强的关联。然而，lncRNA 控制 ApoC3 表达的确切机制尚不清楚。
我们在载脂蛋白 A1/C3/A4/A5 基因簇内鉴定了一种新的长非编码 RNA（lncRNA）GM47544。随后，分析了 GM47544 对细胞内甘油三酯代谢的影响。建立了饮食诱导的高脂血症和动脉粥样硬化小鼠模型，以探讨 GM47544 在体内对血脂异常和斑块形成的影响。通过 RNA 测序、免疫沉淀、RNA 下拉实验和 RNA 免疫沉淀实验探讨了分子机制。
GM47544 在高脂肪刺激下表达上调。GM47544 有效地改善了肝脂肪变性，降低了血脂水平，并在体内和体外减轻了动脉粥样硬化。机制上，GM47544 直接与 ApoC3 结合，并促进 ApoC3 赖氨酸 79 上的泛素化，从而通过泛素蛋白酶体途径促进 ApoC3 降解。此外，我们鉴定出 AP006216.5 是人类 GM47544 的转录本，它在人肝细胞中具有类似的功能。
鉴定 GM47544 为 ApoC3 的 lncRNA 调节剂揭示了一种新的翻译后修饰机制，对治疗高甘油三酯血症和动脉粥样硬化具有重要的临床意义。
