Available online 30 July 2022, 111722
Highlights•3930402G23Rik (G23Rik) is a liver-enriched lncRNA.
•G23Rik is a PPARA target gene.
•Loss of G23Rik increases hepatic lipid accumulation during fasting.
AbstractPeroxisome 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.
KeywordsPPARA
LncRNA
G23Rik
Fasting
AbbreviationsAcot1encoding acyl-CoA thioesterase 1
Acox1encoding acyl-Co-A oxidase 1
ALTalanine aminotransferase
ASTaspartate aminotransferase
Cyp2a4cytochrome P450 family 2 subfamily a member 4
free fatty acid receptor-3G23Rik−/−
G23Rik knockout miceG23Rik
lncRNA 3930402G23RikHIF1α
hypoxia-inducible factor 1αLcn2
lipocalin 2Long non-coding RNAs (lncRNAs) NEFA
non-esterified fatty acidsOrm2
orosomucoid 2Ppara−/−
PPARα knockout mice PPARαperoxisome proliferator-activated receptor α
PPREperoxisome proliferator response elements
UPLC-ESI-QTOFMSUPLC-electrospray ionization-quadrupole time-of-flight mass spectrometry
View full textPublished by Elsevier B.V.
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