Key result
Depletion of lncRHL induces hepatic VLDL secretion and decreases hepatic lipid contents, while its restoration reduces VLDL secretion and increases lipid deposition in hepatocytes.
Why the study?
Dysregulation of hepatic VLDL secretion contributes to NAFLD and hyperlipidemia, but the function of lncRNAs in controlling hepatic VLDL secretion remains largely unillustrated.
Identification of lncRHL as a novel suppressor of hepatic VLDL secretion suggests the lncRHL/hnRNPU/BMAL1/MTTP axis as a potential therapeutic target for lipid homeostasis.
lncRHL identification is hypothesis-generating for VLDL secretion in NAFLD; leaves open therapeutic relevance pending validation.
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.
No takes yet. Share an insight, caveat, or question.
Shen et al. (2022) studied Nonalcoholic fatty liver disease (NAFLD) and hyperlipidemia. lncRHL genetic manipulation was evaluated on Hepatic VLDL secretion and hepatic lipid contents. Depletion of lncRHL induces hepatic VLDL secretion and decreases hepatic lipid contents, while its restoration reduces VLDL secretion and increases lipid deposition in hepatocytes.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: