Journal
MOLECULAR AND CELLULAR ENDOCRINOLOGY
Volume 557, Issue -, Pages -Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.mce.2022.111722
Keywords
PPARA; LncRNA; G23Rik; Fasting
Categories
Funding
- National Cancer Institute, National Institutes of Health Intramural Research Program
- NIH [ES024421]
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PPARα plays a crucial role in modulating metabolic stress and inflammation in the liver through its regulation of lncRNA G23Rik, which attenuates hepatic lipid accumulation.
Peroxisome proliferator-activated receptor alpha (PPAR alpha) is a key mediator of lipid metabolism and metabolic stress in the liver. A recent study revealed that PPAR alpha-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 PPAR alpha. Although G23Rik RNA was expressed to varying degrees in several tissues, the PPAR alpha-dependent regulation of this lncRNA was only observed in the liver. Pharmacological acti-vation of PPAR alpha induced PPAR alpha 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 enhanced 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 PPAR alpha attenuates hepatic lipid accumulation in response to metabolic stress through lncRNA G23Rik induction.
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