A liver-enriched long non-coding RNA, lncLSTR, regulates systemic lipid metabolism in mice

Area of Science:

• Molecular Biology
• Genomics
• Lipid Metabolism

Background:

• Long non-coding RNAs (lncRNAs) are abundant but their physiological roles remain largely uncharacterized.
• Understanding lncRNA functions is crucial for deciphering complex biological processes.
• The liver's role in systemic lipid homeostasis is central to metabolic health.

Purpose of the Study:

• To identify and characterize novel lncRNAs involved in liver lipid metabolism.
• To elucidate the molecular mechanisms by which lncRNAs regulate triglyceride levels.
• To explore the therapeutic potential of targeting lncRNAs for hyperlipidemia.

Main Methods:

• Identification of a novel liver-enriched lncRNA, lncLSTR, in mice.
• Conditional depletion of lncLSTR in the liver using genetic models.
• Analysis of plasma triglyceride levels and lipoprotein lipase activity.
• Investigation of apoC2 and Cyp8b1 gene expression.
• Exploration of the FXR-mediated pathway and TDP-43 complex formation.
• Assessment of lncLSTR depletion in a hyperlipidemia mouse model.

Main Results:

• Liver-specific depletion of lncLSTR significantly reduces plasma triglyceride levels.
• lncLSTR depletion upregulates apoC2 expression, enhancing lipoprotein lipase activity and triglyceride clearance.
• lncLSTR regulates Cyp8b1 expression via a TDP-43 complex, influencing bile acid pools and FXR activation.
• lncLSTR depletion effectively lowers triglyceride levels in a hyperlipidemia mouse model.

Conclusions:

• lncLSTR is a key regulator of hepatic triglyceride metabolism.
• lncLSTR modulates lipid homeostasis through a TDP-43/FXR/apoC2 signaling axis.
• Targeting lncLSTR presents a potential therapeutic strategy for managing hyperlipidemia.