Upregulation of miR-125b by estrogen protects against non-alcoholic fatty liver in female mice.
OBJECTIVE
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.


CONCLUSIONS
Our findings identify a novel mechanism by which estrogen protects against hepatic steatosis in female mice via upregulating miR-125b expression.
Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai 200032, PR China.
Zhi-Chun
ZC
Zhang
Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai 200032, PR China.
Yan
Y
Liu
Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai 200032, PR China.
Liu-Ling
LL
Xiao
Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai 200032, PR China.
Shu-Fen
SF
Li
Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai 200032, PR China.
Jing-Hui
JH
Jiang
Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai 200032, PR China.
Yue
Y
Zhao
Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai 200032, PR China.
Shu-Wen
SW
Qian
Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai 200032, PR China; Institute of Stem Cell and Regenerative Medicine, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, PR China.
Qi-Qun
QQ
Tang
Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai 200032, PR China. Electronic address: lixi@shmu.edu.cn.
Xi
X
Li
D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism*; D064429:Fatty Acid Synthases / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D056945:Hep G2 Cells; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D010052:Ovariectomy; D015854:Up-Regulation
D047628:Estrogen Receptor alpha; D004967:Estrogens; D035683:MicroRNAs; C527468:Mirn125 microRNA, mouse; D064429:Fatty Acid Synthases
Estrogen; FAS; Lipogenesis; NAFLD; Premenopause; miR-125b