Dysregulation of hepatic very low-density lipoprotein (VLDL) secretion contributes to the pathogenesis of metabolic diseases, such as Non-alcoholic fatty liver disease (NAFLD) and hyperlipidemia. Accumulating evidence have suggested that long non-coding RNAs (lncRNAs) had malfunctioning roles in the pathogenesis of NAFLD. However, the function of lncRNAs in controlling hepatic VLDL secretion remains largely unillustrated. Here, we identified a novel long non-coding RNA, lncRHL, which was liver-enriched, downregulated upon high fat diet feeding, and inhibited by oleic acid treatment in primary hepatocytes. With genetic manipulation in mice and primary hepatocytes, depletion of lncRHL induces hepatic VLDL secretion accompanied with decreased hepatic lipid contents. Conversely, lncRHL restoration reduces VLDL secretion with an increased lipid deposition in hepatocytes. Mechanistic analyses indicate that lncRHL binds directly to heterogeneous nuclear ribonuclear protein U (hnRNPU), thereby enhances its stability, and that hnRNPU can transcriptional activate Bmal1, leading to inhibition of VLDL secretion in hepatocytes. lncRHL deficiency accelerates the protein degradation of hnRNPU and suppresses the transcription of Bmal1, which in turn activates VLDL secretion in hepatocytes. Taken together, lncRHL is a novel suppressor of hepatic VLDL secretion. Activating the lncRHL/hnRNPU/Bmal1/MTTP axis represent a potential strategy for the maintenance of intrahepatic and plasma lipid homeostasis.

中文翻译：

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长链非编码 RNA lncRHL 通过调节 hnRNPU/BMAL1/MTTP 轴调节肝脏 VLDL 分泌

肝脏极低密度脂蛋白 (VLDL) 分泌失调有助于代谢疾病的发病机制，例如非酒精性脂肪肝 (NAFLD) 和高脂血症。越来越多的证据表明，长链非编码 RNA (lncRNA) 在 NAFLD 的发病机制中发挥了失常的作用。然而，lncRNAs 在控制肝脏 VLDL 分泌中的作用在很大程度上仍未阐明。在这里，我们鉴定了一种新的长链非编码 RNA，lncRHL，它富含肝脏，在高脂肪饮食喂养时下调，并在原代肝细胞中被油酸处理抑制。通过对小鼠和原代肝细胞的基因操作，lncRHL 的消耗诱导肝脏 VLDL 分泌，同时肝脏脂质含量降低。反过来，lnc RHL 恢复减少 VLDL 分泌，肝细胞中脂质沉积增加。机制分析表明，lncRHL直接与异质核核糖核蛋白U（hnRNPU）结合，从而增强其稳定性，并且hnRNPU可以转录激活Bmal1，从而抑制肝细胞中VLDL的分泌。lnc RHL 缺乏会加速 hnRNPU 的蛋白质降解并抑制 Bmal1 的转录，进而激活肝细胞中 VLDL 的分泌。总之，lncRHL 是一种新型的肝脏 VLDL 分泌抑制剂。激活 lncRHL/hnRNPU/Bmal1/MTTP 轴代表了维持肝内和血浆脂质稳态的潜在策略。从而增强其稳定性，并且hnRNPU可以转录激活Bmal1，从而抑制肝细胞中VLDL的分泌。lnc RHL 缺乏会加速 hnRNPU 的蛋白质降解并抑制 Bmal1 的转录，进而激活肝细胞中 VLDL 的分泌。总之，lncRHL 是一种新型的肝脏 VLDL 分泌抑制剂。激活 lncRHL/hnRNPU/Bmal1/MTTP 轴代表了维持肝内和血浆脂质稳态的潜在策略。从而增强其稳定性，并且hnRNPU可以转录激活Bmal1，从而抑制肝细胞中VLDL的分泌。lnc RHL 缺乏会加速 hnRNPU 的蛋白质降解并抑制 Bmal1 的转录，进而激活肝细胞中 VLDL 的分泌。总之，lncRHL 是一种新型的肝脏 VLDL 分泌抑制剂。激活 lncRHL/hnRNPU/Bmal1/MTTP 轴代表了维持肝内和血浆脂质稳态的潜在策略。lncRHL 是一种新型的肝脏 VLDL 分泌抑制剂。激活 lncRHL/hnRNPU/Bmal1/MTTP 轴代表了维持肝内和血浆脂质稳态的潜在策略。lncRHL 是一种新型的肝脏 VLDL 分泌抑制剂。激活 lncRHL/hnRNPU/Bmal1/MTTP 轴代表了维持肝内和血浆脂质稳态的潜在策略。