MicroRNA-27b is a regulatory hub in lipid metabolism and is altered in dyslipidemia§

Authors

  • Kasey C. Vickers,

    1. Lipoprotein Metabolism Section, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD
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  • Bassem M. Shoucri,

    1. Lipoprotein Metabolism Section, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD
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  • Michael G. Levin,

    1. Lipoprotein Metabolism Section, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD
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  • Han Wu,

    1. DNA Sequencing and Computational Biology Core, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD
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  • Daniel S. Pearson,

    1. Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD
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  • David Osei-Hwedieh,

    1. Lipoprotein Metabolism Section, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD
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  • Francis S. Collins,

    1. Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD
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  • Alan T. Remaley,

    1. Lipoprotein Metabolism Section, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD
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    • These authors contributed equally to this work.

  • Praveen Sethupathy

    Corresponding author
    1. Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC
    2. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC
    • Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC
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    • These authors contributed equally to this work.

    • fax: 919-843-4682


  • Potential conflict of interest: Nothing to report.

  • Supported by the intramural programs of the National Human Genome Research Institute (NHGRI) and the National Heart, Lung, and Blood Institute (NHLBI), a K22 grant HL113039-01 (to K.C.V.) from the NHLBI, and an R00 grant 4R00DK091318-02 (to P.S.) from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

  • See Editorial on Page 432

Abstract

Cellular and plasma lipid levels are tightly controlled by complex gene regulatory mechanisms. Elevated plasma lipid content, or hyperlipidemia, is a significant risk factor for cardiovascular morbidity and mortality. MicroRNAs (miRNAs) are posttranscriptional regulators of gene expression and have emerged as important modulators of lipid homeostasis, but the extent of their role has not been systematically investigated. In this study we performed high-throughput small RNA sequencing and detected ≈150 miRNAs in mouse liver. We then employed an unbiased, in silico strategy to identify miRNA regulatory hubs in lipid metabolism, and miR-27b was identified as the strongest such hub in human and mouse liver. In addition, hepatic miR-27b levels were determined to be sensitive to plasma hyperlipidemia, as evidenced by its ≈3-fold up-regulation in the liver of mice on a high-fat diet (42% calories from fat). Further, we showed in a human hepatocyte cell line (Huh7) that miR-27b regulates the expression (messenger RNA [mRNA] and protein) of several key lipid-metabolism genes, including Angptl3 and Gpam. Finally, we demonstrated that hepatic miR-27b and its target genes are inversely altered in a mouse model of dyslipidemia and atherosclerosis. Conclusion: miR-27b is responsive to lipid levels and controls multiple genes critical to dyslipidemia. (HEPATOLOGY 2013)

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