Background & Aims
Due to the protective effect of estrogen against hepatic fat accumulation, the prevalence
of non-alcoholic fatty liver disease (NAFLD) in premenopausal women is lower than
that in men at the same age and in postmenopausal women. Our study was to further
elucidate an underlying mechanism by which estrogen prevents NAFLD from miRNA perspective
in female mice.
Methods
miRNA expression was evaluated by TaqMan miRNA assay. Luciferase and ChIP assay were
done to validate regulation of miR-125b by estrogen via estrogen receptor alpha (ERα).
Nile red and Oil red O staining were used to check lipid content. Overexpressing or
inhibiting the physiological role of miR-125b in the liver of mice through injecting
adenovirus were used to identify the function of miR-125b in vivo.
Results
miR-125b expression was activated by estrogen via ERα in vitro and in vivo. miR-125b inhibited lipid accumulation both in HepG2 cells and primary mouse hepatocytes.
Consistently, ovariectomized or liver-specific ERα knockdown mice treated with miR-125b
overexpressing adenoviruses were resistant to hepatic steatosis induced by high-fat
diet, due to decreased fatty acid uptake and synthesis and decreased triglyceride
synthesis. Conversely, inhibiting the physiological role of miR-125b with a sponge
decoy slightly promoted liver steatosis with a high-fat diet. Notably, we provided
evidence showing that fatty acid synthase was a functional target of miR-125b.
Conclusion
Our findings identify a novel mechanism by which estrogen protects against hepatic
steatosis in female mice via upregulating miR-125b expression.
Graphical abstract
Graphical Abstract
Abbreviations:
NAFLD (non-alcoholic fatty liver disease), ChIP (chromatin immunoprecipitation), HFD (high-fat diet), ALT (alanine aminotransferase), AST (aspartate aminotransferase), FFA (free fatty acid), FAS (fatty acid synthase), SCD1 (stearoyl coenzyme A desaturase 1), SREBP-1C (sterol regulatory element binding protein 1C), ACC (acetyl coenzyme A carboxylase), PPAR (peroxisome proliferator-activated receptor), LXRα (liver X receptor alpha), DGAT (diacylglycerol acyl coenzyme A acyltransferase), CPT1 (carnitine palmitoyltransferase 1), MCD (malonyl coenzyme A decarboxylase), LCAD (long-chain acyl coenzyme A dehydrogenase), UCP2 (uncoupling protein 2), NC (negative control), WAT (white adipose tissue), TG (triglyceride), ERE (estrogen response element)Keywords
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Article info
Publication history
Published online: August 10, 2015
Accepted:
July 29,
2015
Received in revised form:
July 12,
2015
Received:
March 2,
2015
Identification
Copyright
© 2015 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.
