Available online 30 July 2022, 111722

Highlights•

3930402G23Rik (G23Rik) is a liver-enriched lncRNA.

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G23Rik is a PPARA target gene.

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Loss of G23Rik increases hepatic lipid accumulation during fasting.

Abstract

Peroxisome proliferator-activated receptor α (PPARα) is a key mediator of lipid metabolism and metabolic stress in the liver. A recent study revealed that PPARα-dependent long non-coding RNAs (lncRNAs) play an important role in modulating metabolic stress and inflammation in the livers of fasted mice. Here hepatic lncRNA 3930402G23Rik (G23Rik) was found to have active peroxisome proliferator response elements (PPREs) within its promoter and is directly regulated by PPARα. Although G23Rik RNA was expressed to varying degrees in several tissues, the PPARα-dependent regulation of this lncRNA was only observed in the liver. Pharmacological activation of PPARα induced PPARα recruitment at the G23Rik promoter and a pronounced increase in hepatic G23Rik lncRNA expression. A G23Rik-null mouse line was developed to further characterize the function of this lncRNA in the liver. G23Rik-null mice were more susceptible to hepatic lipid accumulation in response to acute fasting. Histological analysis further revealed a pronounced buildup of lipid droplets and a significant increase in neutral triglycerides and lipids as indicated by enhance oil red O staining of liver sections. Hepatic cholesterol, non-esterified fatty acid, and triglyceride levels were significantly elevated in G23Rik-null mice and associated with induction of the lipid-metabolism related gene Cd36. These findings provide evidence for a lncRNA dependent mechanism by which PPARα attenuates hepatic lipid accumulation in response to metabolic stress through lncRNA G23Rik induction.

Keywords

PPARA

LncRNA

G23Rik

Fasting

AbbreviationsAcot1

encoding acyl-CoA thioesterase 1

Acox1

encoding acyl-Co-A oxidase 1

ALT

alanine aminotransferase

AST

aspartate aminotransferase

Cyp2a4

cytochrome P450 family 2 subfamily a member 4

free fatty acid receptor-3

G23Rik−/−

G23Rik knockout mice

G23Rik

lncRNA 3930402G23Rik

HIF1α

hypoxia-inducible factor 1α

Lcn2

lipocalin 2

Long non-coding RNAs (lncRNAs) NEFA

non-esterified fatty acids

Orm2

orosomucoid 2

Ppara−/−

PPARα knockout mice PPARα

peroxisome proliferator-activated receptor α

PPRE

peroxisome proliferator response elements

UPLC-ESI-QTOFMS

UPLC-electrospray ionization-quadrupole time-of-flight mass spectrometry

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Published by Elsevier B.V.