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

Area of Science:

• Molecular Biology
• Metabolic Disease Research
• RNA Biology

Background:

• Hepatic very-low-density lipoprotein (VLDL) secretion is implicated in metabolic disorders like NAFLD and hyperlipidemia.
• Long noncoding RNAs (lncRNAs) are increasingly recognized for their roles in NAFLD pathogenesis, but their specific functions in regulating hepatic VLDL secretion are not well understood.

Purpose of the Study:

• To identify and characterize novel lncRNAs involved in the regulation of hepatic VLDL secretion.
• To elucidate the molecular mechanisms by which lncRNAs control VLDL production and secretion in hepatocytes.

Main Methods:

• Identification of a novel liver-enriched lncRNA, termed lncRNA regulator of hyperlipidemia (lncRHL).
• In vivo and in vitro studies using genetic manipulation (depletion and restoration) in mice and primary hepatocytes.
• Mechanistic investigations involving protein-RNA interactions, protein stability assays, and transcriptional analysis.

Main Results:

• lncRHL expression is downregulated by high-fat diet and oleic acid.
• Depletion of lncRHL increases hepatic VLDL secretion and decreases hepatic lipid content.
• lncRHL stabilizes hnRNPU, which transcriptionally activates Bmal1, thereby inhibiting VLDL secretion. lncRHL deficiency leads to hnRNPU degradation and suppressed Bmal1 transcription, promoting VLDL secretion.

Conclusions:

• lncRHL acts as a novel suppressor of hepatic VLDL secretion.
• The lncRHL/hnRNPU/BMAL1/MTTP axis is a key regulator of intrahepatic and plasma lipid homeostasis.
• Targeting the lncRHL pathway offers a potential therapeutic strategy for metabolic diseases characterized by dyslipidemia.