Long Noncoding RNA lncRHPL Regulates Hepatic VLDL Secretion by Modulating hnRNPU/BMAL1/MTTP Axis

Abstract

<p>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, lncRHPL, 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 lncRHPL induces hepatic VLDL secretion accompanied with decreased hepatic lipid contents. Conversely, lncRHPL restoration reduces VLDL secretion with an increased lipid deposition in hepatocytes. Mechanistic analyses indicate that lncRHPL 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. lncRHPL deficiency accelerates the protein degradation of hnRNPU and suppresses the transcription of Bmal1, which in turn activates VLDL secretion in hepatocytes. Taken together, lncRHPL is a novel suppressor of hepatic VLDL secretion. Activating the lncRHPL/hnRNPU/Bmal1/MTTP axis represent a potential strategy for the maintenance of intrahepatic and plasma lipid homeostasis. </p>