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DB211145 suppl material_rev_final.pdf (37.57 MB)

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

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Version 2 2023-03-31, 19:59
Version 1 2022-06-30, 18:49
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posted on 2023-03-31, 19:59 authored by Xuan SHEN, Yajun ZHANG, Xuetao JI, Bo LI, Yuzhu WANG, Yun Huang, Xu ZHANG, Jingxian YU, Ruihan ZOU, Dongdong QIN, Hongwen ZHOU, Qian WANG, John Zhong LI

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. 

Funding

This work was supported by grants from the National Key R&D Program of China [grant number 2018YFA0506904 to J.Z.L]; the National Natural Science Foundation of China [grant numbers 32130050, 31771307, 91957115, 81471079 to J.Z.L. 81770859 to Q.W.]; and the Jiangsu Provincial Innovation Team Program Foundation.

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