期刊
DIABETES
卷 71, 期 9, 页码 1915-1928出版社
AMER DIABETES ASSOC
DOI: 10.2337/db21-1145
关键词
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资金
- National Key R&D Program of China [2018YFA0506904]
- National Natural Science Foundation of China [32130050, 31771307, 91957115, 81471079, 81770859]
- Jiangsu Provincial Innovation Team Program Foundation
A novel lncRNA regulator of hyperlipidemia (lncRHL) was identified in this study, showing differential expression in the liver under high-fat diet and oleic acid treatment, and regulating hepatic VLDL secretion. This lncRNA maintains intrahepatic and plasma lipid homeostasis by modulating the hnRNPU/BMAL1/MTTP axis.
Dysregulation of hepatic VLDL secretion contributes to the pathogenesis of metabolic diseases, such as nonalcoholic fatty liver disease (NAFLD) and hyperlipidemia. Accumulating evidence has suggested that long noncoding 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 lncRNA, lncRNA regulator of hyperlipidemia (lncRHL), which was liver-enriched, downregulated on 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 by decreased hepatic lipid contents. Conversely, lncRHL restoration reduces VLDL secretion with increased lipid deposition in hepatocytes. Mechanistic analyses indicate that lncRHL binds directly to heterogeneous nuclear ribonuclear protein U (hnRNPU), and 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. With results taken together, we conclude that lncRHL is a novel suppressor of hepatic VLDL secretion. Activating the lncRHL/hnRNPU/BMAL1/MTTP axis represents a potential strategy for the maintenance of intrahepatic and plasma lipid homeostasis.
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