Non-alcohol fatty liver disease (NAFLD) is considered to be the hepatic manifestation of the metabolic syndrome. NAFLD occurs mainly due to the fat accumulation in the liver, and can lead to cirrhosis, which is not reversible and may ultimately progress to hepatocellular carcinoma.
The previous reports showed that estrogen protects against hepatic steatosis. The risk of developing NAFLD markedly increases in postmenopausal women and men. The hormone (estrogen) replacement therapy might be one consideration for prevention or treatment of NAFLD, but estrogen may lead to side effects like breast cancer. And we can’t treat men with estrogen against NAFLD.
Here, we firstly demonstrated that estrogen could regulate miR-125b expression via estrogen receptor alpha and that miR-125b could inhibit lipid accumulation in vitro and in vivo. Notably, we discovered FAS as a novel functional target of miR-125b. We demonstrated the function of miR-125b on limiting fat accumulation and inflammatory insults in the liver of both male and females, providing new understanding of a molecular mechanism underlying hepatic steatosis.
We identify a novel mechanism that estrogen protects against hepatic steatosis in female mice by miR-125b and provide a potential treatment strategy for metabolic disorders.
J Hepatol. 2015. pii: S0168-8278(15)00541-3.
Zhang ZC1, Liu Y1, Xiao LL1, Li SF1, Jiang JH1, Zhao Y1, Qian SW1, Tang QQ2, Li X3.[expand title=”Show Affiliations”]
- 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.
- 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.
- 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: [email protected]
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.
miRNA expression was evaluated by TaqMan miRNA assay. Luciferase and ChIP assay were done to validate regulation of miR-125bby 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.
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.
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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