Inhibition of microRNA-24 expression in liver prevents hepatic lipid accumulation and hyperlipidemia

Authors

  • Raymond Ng,

    1. Agency for Science Technology and Research, Singapore
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  • Heng Wu,

    1. Department of Medicine, University of Minnesota Medical School, Minneapolis, MN
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  • Hong Xiao,

    1. Department of Medicine, University of Minnesota Medical School, Minneapolis, MN
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  • Xin Chen,

    1. Departments of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA
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  • Holger Willenbring,

    1. Department of Surgery, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, and Liver Center, University of California, San Francisco, San Francisco, CA
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  • Clifford J. Steer,

    1. Department of Medicine, University of Minnesota Medical School, Minneapolis, MN
    2. Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN
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  • Guisheng Song

    Corresponding author
    1. Department of Medicine, University of Minnesota Medical School, Minneapolis, MN
    • Address reprint requests to: Guisheng Song, Ph.D., Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Minnesota Medical School, MMC 36, VFW Cancer Research Center, V354, 406 Harvard St. SE, Minneapolis MN 55455, E-mail: gsong@umn.edu, fax: 612-625-5620.

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  • Potential conflict of interest: Nothing to report.

  • Supported in part from grants received from the Department of Medicine, Minnesota Medical Foundation, NIH Clinical and Translational Science Award at the University of Minnesota (UL1TR000114), and Grants-in-Aid from the University of Minnesota.

Abstract

The incidence of nonalcoholic fatty liver disease (NAFLD) and hyperlipidemia, with their associated risks of endstage liver and cardiovascular diseases, is increasing rapidly due to the prevalence of obesity. Although the mechanisms of NAFLD have been studied extensively, the underlying pathogenesis and the role of microRNAs in this process remain relatively unclear. MicroRNA (miRNA)-dependent posttranscriptional gene silencing is now recognized as a key element of lipid metabolism. Here we report that the expression of microRNA-24 (miR-24) is significantly increased in the livers of high-fat diet-treated mice and in isolated human hepatocytes incubated with fatty acid. Knockdown of miR-24 in those mice caused impaired hepatic lipid accumulation and reduced plasma triglycerides. Bioinformatic and in vitro and in vivo studies led us to identify insulin-induced gene 1 (Insig1), an inhibitor of lipogenesis, as a novel target of miR-24. Inhibition of endogenous miR-24 expression by way of miR-24 inhibitors led to up-regulation of Insig1, and subsequently decreased hepatic lipid accumulation. It is well established that liver-specific deletion of Insig1 leads to higher hepatic and plasma triglyceride levels by inhibiting the processing of sterol regulatory element-binding proteins (SREBPs), transcription factors that activate lipid synthesis. As expected, miR-24 knockdown prevented SREBP processing, and subsequent expression of lipogenic genes. In contrast, the opposite result was observed with overexpression of miR-24, which enhanced SREBP processing. Thus, our study defines a potentially critical role for deregulated expression of miR-24 in the development of fatty liver by way of targeting of Insig1. Conclusion: Our findings show a novel mechanism by which miR-24 promotes hepatic lipid accumulation and hyperlipidemia by repressing Insig1, and suggest the use of miR-24 inhibitor as a potential therapeutic agent for NAFLD and/or atherosclerosis. (Hepatology 2014;60:554–564)

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