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.
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