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Thromb Haemost 2012; 107(04): 642-647
DOI: 10.1160/TH11-10-0694
Theme Issue Article
Schattauer GmbH

MicroRNAs regulating lipid metabolism in atherogenesis

Katey J. Rayner
1   Department of Medicine and Cell Biology, New York University School of Medicine, New York, New York, USA
2   Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, New York, USA
3   Marc and Ruti Bell Vascular Biology and Disease Program, New York University School of Medicine, New York, New York, USA
,
Carlos Fernández-Hernando
1   Department of Medicine and Cell Biology, New York University School of Medicine, New York, New York, USA
2   Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, New York, USA
3   Marc and Ruti Bell Vascular Biology and Disease Program, New York University School of Medicine, New York, New York, USA
,
Kathryn J. Moore
1   Department of Medicine and Cell Biology, New York University School of Medicine, New York, New York, USA
2   Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, New York, USA
3   Marc and Ruti Bell Vascular Biology and Disease Program, New York University School of Medicine, New York, New York, USA
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Publikationsverlauf

Received: 06. Oktober 2011

Accepted after minor revision: 24. Januar 2011

Publikationsdatum:
29. November 2017 (online)

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Summary

MicroRNAs have emerged as important post-transcriptional regulators of lipid metabolism, and represent a new class of targets for therapeutic intervention. Recently, microRNA-33a and b (miR-33a/b) were discovered as key regulators of metabolic programs including cholesterol and fatty acid homeostasis. These intronic microRNAs are embedded in the sterol response element binding protein genes, SREBF2 and SREBF1, which code for transcription factors that coordinate cholesterol and fatty acid synthesis. By repressing a variety of genes involved in cholesterol export and fatty acid oxidation, including ABCA1, CROT, CPT1, HADHB and PRKAA1, miR-33a/b act in concert with their host genes to boost cellular sterol levels. Recent work in animal models has shown that inhibition of these small non-coding RNAs has potent effects on lipoprotein metabolism, including increasing plasma high-density lipo-protein (HDL) and reducing very low density lipoprotein (VLDL) triglyce-rides. Furthermore, other microRNAs are being discovered that also target the ABCA1 pathway, including miR-758, suggesting that miRNAs may work cooperatively to regulate this pathway. These exciting findings support the development of microRNA antagonists as potential therapeutics for the treatment of dyslipidaemia, atherosclerosis and related metabolic diseases.

Keywords

Atherosclerosis - lipoproteins - microRNA
 

  • References

  • 1 Ambros V. MicroRNA pathways in flies and worms: growth, death, fat, stress, and timing. Cell 2003; 113: 673-676.
    CrossrefPubMedGoogle Scholar
  • 2 Ambros V. The functions of animal microRNAs. Nature 2004; 431: 350-355.
    CrossrefPubMedGoogle Scholar
  • 3 Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell 2009; 136: 215-233.
    CrossrefPubMedGoogle Scholar
  • 4 Filipowicz W, Bhattacharyya SN, Sonenberg N. Mechanisms of post-transcrip-tional regulation by microRNAs: are the answers in sight?. Nat Rev Genet 2008; 09: 102-114.
    CrossrefPubMedGoogle Scholar
  • 5 Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 1993; 75: 843-854.
    CrossrefPubMedGoogle Scholar
  • 6 Wightman B, Ha I, Ruvkun G. Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans. Cell 1993; 75: 855-862.
    CrossrefPubMedGoogle Scholar
  • 7 Marquart TJ, Allen RM, Ory DS. et al. miR-33 links SREBP-2 induction to repression of sterol transporters. Proc Natl Acad Sci USA 2010; 107: 12228-12232.
    CrossrefPubMedGoogle Scholar
  • 8 Najafi-Shoushtari SH, Kristo F, Li Y. et al. MicroRNA-33 and the SREBP host genes cooperate to control cholesterol homeostasis. Science 2010; 328: 1566-1569.
    CrossrefPubMedGoogle Scholar
  • 9 Rayner KJ, Suarez Y, Davalos A. et al. MiR-33 contributes to the regulation of cholesterol homeostasis. Science 2010; 328: 1570-1573.
    CrossrefPubMedGoogle Scholar
  • 10 Horton JD, Goldstein JL, Brown MS. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest 2002; 109: 1125-1131.
    CrossrefPubMedGoogle Scholar
  • 11 Walker AK, Yang F, Jiang K. et al. Conser ved role of SIRT1 or thologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP. Genes Devel 2010; 24: 1403-1417.
    CrossrefPubMedGoogle Scholar
  • 12 Davalos A, Goedeke L, Smibert P. et al. miR-33a/b contribute to the regulation of fatty acid metabolism and insulin signaling. Proc Natl Acad Sci USA 2011; 108: 9232-9237.
    CrossrefPubMedGoogle Scholar
  • 13 Gerin I, Clerbaux LA, Haumont O. et al. Expression of miR-33 from an SREBP2 intron inhibits cholesterol export and fatty acid oxidation. J Biol Chem 2010; 285: 33652-33661.
    CrossrefPubMedGoogle Scholar
  • 14 Rayner KJ, Sheedy FJ, Esau CC. et al. Antagonism of miR-33 in mice promotes reverse cholesterol transport and regression of atherosclerosis. J Clin Invest 2011; 121: 2921-22931.
    CrossrefPubMedGoogle Scholar
  • 15 Rodriguez A, Griffiths-Jones S, Ashurst JL. et al. Identification of mammalian microRNA host genes and transcription units. Genome Res 2004; 14: 1902-1910.
    CrossrefPubMedGoogle Scholar
  • 16 Tall AR, Yvan-Charvet L, Terasaka N. et al. HDL, ABC transporters, and cholesterol efflux: implications for the treatment of atherosclerosis. Cell Metab 2008; 07: 365-375.
    CrossrefPubMedGoogle Scholar
  • 17 Wang MD, Franklin V, Sundaram M. et al. Differential regulation of ATP binding cassette protein A1 expression and ApoA-I lipidation by Niemann-Pick type C1 in murine hepatocytes and macrophages. J Biol Chem 2007; 282: 22525-22533.
    CrossrefPubMedGoogle Scholar
  • 18 Alberti KG, Eckel RH, Grundy SM. et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 2009; 120: 1640-1645.
    CrossrefPubMedGoogle Scholar
  • 19 Geary RS. Antisense oligonucleotide pharmacokinetics and metabolism. Expert Opin Drug Metab Toxicol 2009; 05: 381-391.
    CrossrefPubMedGoogle Scholar
  • 20 Horie T, Ono K, Horiguchi M. et al. MicroRNA-33 encoded by an intron of sterol regulatory element-binding protein 2 (Srebp2) regulates HDL in vivo. Proc Natl Acad Sci USA 2010; 107: 17321-17326.
    CrossrefPubMedGoogle Scholar
  • 21 Degoma EM, Rader DJ. Novel HDL-directed pharmacotherapeutic strategies. Nature Rev Cardiol 2011; 08: 266-277.
    CrossrefPubMedGoogle Scholar
  • 22 Rayner KJ, Esau CC, Hussain FN. et al. Inhibition of miR-33a/b in non-human primates raises plasma HDL and lowers VLDL tr iglycer ides. Nature 2011; 478: 404-407.
    CrossrefPubMedGoogle Scholar
  • 23 Ramirez CM, Davalos A, Goedeke L. et al. MicroRNA-758 Regulates Cholesterol Efflux Through Posttranscriptional Repression of ATP-Binding Cassette Transporter A1. Arterioscl Thromb Vasc Biol 2011; 31: 2707-2714.
    CrossrefPubMedGoogle Scholar
  • 24 Fan J, Donkin J, Wellington C. Greasing the wheels of Abeta clearance in Alzheimer's disease: the role of lipids and apolipoprotein E. Biofactors 2009; 35: 239-248.
    CrossrefPubMedGoogle Scholar
  • 25 Esau C, Davis S, Murray SF. et al. miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell Metab 2006; 03: 87-98.
    CrossrefPubMedGoogle Scholar
  • 26 Elmen J, Lindow M, Silahtaroglu A. et al. Antagonism of microRNA-122 in mice by systemically administered LNA-antimiR leads to up-regulation of a large set of predicted target mRNAs in the liver. Nucleic Acids Res 2008; 36: 1153-1162.
    CrossrefPubMedGoogle Scholar
  • 27 Elmen J, Lindow M, Schutz S. et al. LNA-mediated microRNA silencing in non-human primates. Nature 2008; 452: 896-899.
    CrossrefPubMedGoogle Scholar
  • 28 Lanford RE, Hildebrandt-Eriksen ES, Petri A. et al. Therapeutic silencing of microRNA-122 in primates with chronic hepatitis C virus infection. Science 2010; 327: 198-201.
    CrossrefPubMedGoogle Scholar
  • 29 Jopling CL, Yi M, Lancaster AM. et al. Modulation of hepatitis C virus RNA abundance by a liver-specific MicroRNA. Science 2005; 309: 1577-1581.
    CrossrefPubMedGoogle Scholar
  • 30 Jopling CL, Schutz S, Sarnow P. Position-dependent function for a tandem microRNA miR-122-binding site located in the hepatitis C virus RNA genome. Cell Host Microbe 2008; 04: 77-85.
    CrossrefPubMedGoogle Scholar
  • 31 Randall G, Panis M, Cooper JD. et al. Cellular cofactors affecting hepatitis C virus infection and replication. Proc Natl Acad Sci USA 2007; 104: 12884-12889.
    CrossrefPubMedGoogle Scholar
  • 32 Franciscus A. Hepatitis C Treatments in Current Clinical Development. HCV Advocate 2010 (October 25, 2010). Available at: http://www.hcvadvocate.org/hepatitis/hepc/HCVDrugs.html
    PubMedGoogle Scholar