Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

Science 328 (5985): 1570-1573

Copyright © 2010 by the American Association for the Advancement of Science

MiR-33 Contributes to the Regulation of Cholesterol Homeostasis

Katey J. Rayner,1,2,* Yajaira Suárez,1,* Alberto Dávalos,1 Saj Parathath,1 Michael L. Fitzgerald,2 Norimasa Tamehiro,2 Edward A. Fisher,1 Kathryn J. Moore,1,2,{dagger},{ddagger} Carlos Fernández-Hernando1,{dagger},{ddagger}

Abstract: Cholesterol metabolism is tightly regulated at the cellular level. Here we show that miR-33, an intronic microRNA (miRNA) located within the gene encoding sterol-regulatory element–binding factor–2 (SREBF-2), a transcriptional regulator of cholesterol synthesis, modulates the expression of genes involved in cellular cholesterol transport. In mouse and human cells, miR-33 inhibits the expression of the adenosine triphosphate–binding cassette (ABC) transporter, ABCA1, thereby attenuating cholesterol efflux to apolipoprotein A1. In mouse macrophages, miR-33 also targets ABCG1, reducing cholesterol efflux to nascent high-density lipoprotein (HDL). Lentiviral delivery of miR-33 to mice represses ABCA1 expression in the liver, reducing circulating HDL levels. Conversely, silencing of miR-33 in vivo increases hepatic expression of ABCA1 and plasma HDL levels. Thus, miR-33 appears to regulate both HDL biogenesis in the liver and cellular cholesterol efflux.

1 Departments of Medicine and Cell Biology, Leon H. Charney Division of Cardiology and the Marc and Ruti Bell Vascular Biology and Disease Program, New York University School of Medicine, New York, NY 10016, USA.
2 Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.

* {dagger}These authors contributed equally to this work.

{ddagger} To whom correspondence should be addressed. E-mail: kathryn.moore{at}nyumc.org (K.J.M.); carlos.fernandez-hernando{at}nyumc.org (C.F.-H.)


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Elevated microRNA-155 promotes foam cell formation by targeting HBP1 in atherogenesis.
F.-J. Tian, L.-N. An, G.-K. Wang, J.-Q. Zhu, Q. Li, Y.-Y. Zhang, A. Zeng, J. Zou, R.-F. Zhu, X.-S. Han, et al. (2014)
Cardiovasc Res
   Abstract »    Full Text »    PDF »
Autoregulation of glypican-1 by intronic microRNA-149 fine tunes the angiogenic response to FGF2 in human endothelial cells.
A. Chamorro-Jorganes, E. Araldi, N. Rotllan, D. Cirera-Salinas, and Y. Suarez (2014)
J. Cell Sci. 127, 1169-1178
   Abstract »    Full Text »    PDF »
Regulation of High-Density Lipoprotein Metabolism.
K.-A. Rye and P. J. Barter (2014)
Circ. Res. 114, 143-156
   Abstract »    Full Text »    PDF »
ATP-Binding Cassette Transporters, Atherosclerosis, and Inflammation.
M. Westerterp, A. E. Bochem, L. Yvan-Charvet, A. J. Murphy, N. Wang, and A. R. Tall (2014)
Circ. Res. 114, 157-170
   Abstract »    Full Text »    PDF »
MicroRNA Control of High-Density Lipoprotein Metabolism and Function.
K. J. Rayner and K. J. Moore (2014)
Circ. Res. 114, 183-192
   Abstract »    Full Text »    PDF »
Novel Therapies Focused on the High-Density Lipoprotein Particle.
J. C. van Capelleveen, H. B. Brewer, J. J. P. Kastelein, and G. K. Hovingh (2014)
Circ. Res. 114, 193-204
   Abstract »    Full Text »    PDF »
High-Density Lipoprotein and Atherosclerosis Regression: Evidence From Preclinical and Clinical Studies.
J. E. Feig, B. Hewing, J. D. Smith, S. L. Hazen, and E. A. Fisher (2014)
Circ. Res. 114, 205-213
   Abstract »    Full Text »    PDF »
Endoplasmic reticulum stress impairs cholesterol efflux and synthesis in hepatic cells.
C. Rohrl, K. Eigner, K. Winter, M. Korbelius, S. Obrowsky, D. Kratky, W. J. Kovacs, and H. Stangl (2014)
J. Lipid Res. 55, 94-103
   Abstract »    Full Text »    PDF »
Regulation of ABCA1 Protein Expression and Function in Hepatic and Pancreatic Islet Cells by miR-145.
M. H. Kang, L.-H. Zhang, N. Wijesekara, W. de Haan, S. Butland, A. Bhattacharjee, and M. R. Hayden (2013)
Arterioscler Thromb Vasc Biol 33, 2724-2732
   Abstract »    Full Text »    PDF »
Pharmacological Inhibition of a MicroRNA Family in Nonhuman Primates by a Seed-Targeting 8-Mer AntimiR.
V. Rottiers, S. Obad, A. Petri, R. McGarrah, M. W. Lindholm, J. C. Black, S. Sinha, R. J. Goody, M. S. Lawrence, A. S. deLemos, et al. (2013)
Science Translational Medicine 5, 212ra162
   Abstract »    Full Text »    PDF »
Small RNA Overcomes the Challenges of Therapeutic Targeting of Microsomal Triglyceride Transfer Protein.
K. C. Vickers and K. J. Moore (2013)
Circ. Res. 113, 1189-1191
   Full Text »    PDF »
MiR-9 reduces human acyl-coenzyme A:cholesterol acyltransferase-1 to decrease THP-1 macrophage-derived foam cell formation.
J. Xu, G. Hu, M. Lu, Y. Xiong, Q. Li, C. C. Y. Chang, B. Song, T. Chang, and B. Li (2013)
Acta Biochim Biophys Sin 45, 953-962
   Abstract »    Full Text »    PDF »
The Complexity of Thyroid Transcription Factor 1 with Both Pro- and Anti-oncogenic Activities.
D. Mu (2013)
J. Biol. Chem. 288, 24992-25000
   Abstract »    Full Text »    PDF »
Sterol Regulatory Element Binding Protein 2 Activation of NLRP3 Inflammasome in Endothelium Mediates Hemodynamic-Induced Atherosclerosis Susceptibility.
H. Xiao, M. Lu, T. Y. Lin, Z. Chen, G. Chen, W.-C. Wang, T. Marin, T.-p. Shentu, L. Wen, B. Gongol, et al. (2013)
Circulation 128, 632-642
   Abstract »    Full Text »    PDF »
MicroRNA 33 Regulates Glucose Metabolism.
C. M. Ramirez, L. Goedeke, N. Rotllan, J.-H. Yoon, D. Cirera-Salinas, J. A. Mattison, Y. Suarez, R. de Cabo, M. Gorospe, and C. Fernandez-Hernando (2013)
Mol. Cell. Biol. 33, 2891-2902
   Abstract »    Full Text »    PDF »
Therapeutic Silencing of MicroRNA-33 Inhibits the Progression of Atherosclerosis in Ldlr-/- Mice--Brief Report.
N. Rotllan, C. M. Ramirez, B. Aryal, C. C. Esau, and C. Fernandez-Hernando (2013)
Arterioscler Thromb Vasc Biol 33, 1973-1977
   Abstract »    Full Text »    PDF »
Biomechanical factors and macrophages in plaque stability.
A. Seneviratne, M. Hulsmans, P. Holvoet, and C. Monaco (2013)
Cardiovasc Res 99, 284-293
   Abstract »    Full Text »    PDF »
Nuclear Receptors and microRNA-144 Coordinately Regulate Cholesterol Efflux.
K. C. Vickers and D. J. Rader (2013)
Circ. Res. 112, 1529-1531
   Full Text »    PDF »
Control of Cholesterol Metabolism and Plasma High-Density Lipoprotein Levels by microRNA-144.
C. M. Ramirez, N. Rotllan, A. V. Vlassov, A. Davalos, M. Li, L. Goedeke, J. F. Aranda, D. Cirera-Salinas, E. Araldi, A. Salerno, et al. (2013)
Circ. Res. 112, 1592-1601
   Abstract »    Full Text »    PDF »
MicroRNA-144 Regulates Hepatic ATP Binding Cassette Transporter A1 and Plasma High-Density Lipoprotein After Activation of the Nuclear Receptor Farnesoid X Receptor.
T. Q. de Aguiar Vallim, E. J. Tarling, T. Kim, M. Civelek, A. Baldan, C. Esau, and P. A. Edwards (2013)
Circ. Res. 112, 1602-1612
   Abstract »    Full Text »    PDF »
A Regulatory Role for MicroRNA 33* in Controlling Lipid Metabolism Gene Expression.
L. Goedeke, F. M. Vales-Lara, M. Fenstermaker, D. Cirera-Salinas, A. Chamorro-Jorganes, C. M. Ramirez, J. A. Mattison, R. de Cabo, Y. Suarez, and C. Fernandez-Hernando (2013)
Mol. Cell. Biol. 33, 2339-2352
   Abstract »    Full Text »    PDF »
MicroRNAs 185, 96, and 223 Repress Selective High-Density Lipoprotein Cholesterol Uptake through Posttranscriptional Inhibition.
L. Wang, X.-J. Jia, H.-J. Jiang, Y. Du, F. Yang, S.-Y. Si, and B. Hong (2013)
Mol. Cell. Biol. 33, 1956-1964
   Abstract »    Full Text »    PDF »
A big role for small RNAs in HDL homeostasis.
M. Ouimet and K. J. Moore (2013)
J. Lipid Res. 54, 1161-1167
   Abstract »    Full Text »    PDF »
microRNAs: small regulators with a big impact on lipid metabolism.
K. J. Moore (2013)
J. Lipid Res. 54, 1159-1160
   Full Text »    PDF »
Needles in the genetic haystack of lipid disorders: single nucleotide polymorphisms in the microRNA regulome.
P. Sethupathy (2013)
J. Lipid Res. 54, 1168-1173
   Abstract »    Full Text »    PDF »
Complexity of microRNA function and the role of isomiRs in lipid homeostasis.
K. C. Vickers, P. Sethupathy, J. Baran-Gale, and A. T. Remaley (2013)
J. Lipid Res. 54, 1182-1191
   Abstract »    Full Text »    PDF »
Anti-atherosclerosis or No Anti-atherosclerosis: That is the miR-33 question.
A. M. Naar (2013)
Arterioscler Thromb Vasc Biol 33, 447-448
   Full Text »    PDF »
Anti-miR-33 Therapy Does Not Alter the Progression of Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient Mice.
T. J. Marquart, J. Wu, A. J. Lusis, and A. Baldan (2013)
Arterioscler Thromb Vasc Biol 33, 455-458
   Abstract »    Full Text »    PDF »
MicroRNAs in Metabolic Disease.
C. Fernandez-Hernando, C. M. Ramirez, L. Goedeke, and Y. Suarez (2013)
Arterioscler Thromb Vasc Biol 33, 178-185
   Abstract »    Full Text »    PDF »
miRNAs as Modulators of Angiogenesis.
S. Landskroner-Eiger, I. Moneke, and W. C. Sessa (2013)
Cold Spring Harb Perspect Med 3, a006643
   Abstract »    Full Text »    PDF »
SREBP: a novel therapeutic target.
X. Xiao and B.-L. Song (2013)
Acta Biochim Biophys Sin 45, 2-10
   Abstract »    Full Text »    PDF »
Gene-centric meta-analyses of 108 912 individuals confirm known body mass index loci and reveal three novel signals.
Y. Guo, M. B. Lanktree, K. C. Taylor, H. Hakonarson, L. A. Lange, B. J. Keating, and The IBC 50K SNP array BMI Consortium (2013)
Hum. Mol. Genet. 22, 184-201
   Abstract »    Full Text »    PDF »
High-Density Lipoprotein Function, Dysfunction, and Reverse Cholesterol Transport.
E. A. Fisher, J. E. Feig, B. Hewing, S. L. Hazen, and J. D. Smith (2012)
Arterioscler Thromb Vasc Biol 32, 2813-2820
   Abstract »    Full Text »    PDF »
MicroRNA-33 Deficiency Reduces the Progression of Atherosclerotic Plaque in ApoE-/- Mice.
T. Horie, O. Baba, Y. Kuwabara, Y. Chujo, S. Watanabe, M. Kinoshita, M. Horiguchi, T. Nakamura, K. Chonabayashi, M. Hishizawa, et al. (2012)
JAHA 1, e003376
   Abstract »    Full Text »    PDF »
An Antiatherosclerotic Signaling Cascade Involving Intestinal Microbiota, MicroRNA-10b, and ABCA1/ABCG1-Mediated Reverse Cholesterol Transport.
S. L. Hazen and J. D. Smith (2012)
Circ. Res. 111, 948-950
   Full Text »    PDF »
Gut Microbiota Metabolism of Anthocyanin Promotes Reverse Cholesterol Transport in Mice Via Repressing miRNA-10b.
D. Wang, M. Xia, X. Yan, D. Li, L. Wang, Y. Xu, T. Jin, and W. Ling (2012)
Circ. Res. 111, 967-981
   Abstract »    Full Text »    PDF »
Novel non-coding RNA-based therapeutic approaches to prevent statin-induced liver damage.
C. Bang and T. Thum (2012)
EMBO Mol Med. 4, 863-865
   Full Text »    PDF »
A statin-regulated microRNA represses human c-Myc expression and function.
A. A. L. Takwi, Y. Li, L. E. Becker Buscaglia, J. Zhang, S. Choudhury, A. K. Park, M. Liu, K. H. Young, W.-Y. Park, R. C. G. Martin, et al. (2012)
EMBO Mol Med. 4, 896-909
   Abstract »    Full Text »    PDF »
MicroRNA-143 (miR-143) Regulates Cancer Glycolysis via Targeting Hexokinase 2 Gene.
R. Fang, T. Xiao, Z. Fang, Y. Sun, F. Li, Y. Gao, Y. Feng, L. Li, Y. Wang, X. Liu, et al. (2012)
J. Biol. Chem. 287, 23227-23235
   Abstract »    Full Text »    PDF »
A Novel Regulator of Macrophage Activation: miR-223 in Obesity-Associated Adipose Tissue Inflammation.
G. Zhuang, C. Meng, X. Guo, P. S. Cheruku, L. Shi, H. Xu, H. Li, G. Wang, A. R. Evans, S. Safe, et al. (2012)
Circulation 125, 2892-2903
   Abstract »    Full Text »    PDF »
Primary Prevention of Atherosclerosis: A Clinical Challenge for the Reversal of Epigenetic Mechanisms?.
C. Napoli, V. Crudele, A. Soricelli, M. Al-Omran, N. Vitale, T. Infante, and F. P. Mancini (2012)
Circulation 125, 2363-2373
   Full Text »    PDF »
MicroRNA-26a/b and their host genes cooperate to inhibit the G1/S transition by activating the pRb protein.
Y. Zhu, Y. Lu, Q. Zhang, J.-J. Liu, T.-J. Li, J.-R. Yang, C. Zeng, and S.-M. Zhuang (2012)
Nucleic Acids Res. 40, 4615-4625
   Abstract »    Full Text »    PDF »
Cholesterol Efflux and Atheroprotection: Advancing the Concept of Reverse Cholesterol Transport.
R. S. Rosenson, H. B. Brewer Jr, W. S. Davidson, Z. A. Fayad, V. Fuster, J. Goldstein, M. Hellerstein, X.-C. Jiang, M. C. Phillips, D. J. Rader, et al. (2012)
Circulation 125, 1905-1919
   Full Text »    PDF »
HNF4{alpha} Increases Liver-Specific Human ATP-Binding Cassette Transporter A1 Expression and Cholesterol Efflux to Apolipoprotein A-I in Response to Cholesterol Depletion.
N. Ohoka, K. Okuhira, H. Cui, W. Wu, R. Sato, M. Naito, and T. Nishimaki-Mogami (2012)
Arterioscler Thromb Vasc Biol 32, 1005-1014
   Abstract »    Full Text »    PDF »
miR-33a Modulates ABCA1 Expression, Cholesterol Accumulation, and Insulin Secretion in Pancreatic Islets.
N. Wijesekara, L.-h. Zhang, M. H. Kang, T. Abraham, A. Bhattacharjee, G. L. Warnock, C. B. Verchere, and M. R. Hayden (2012)
Diabetes 61, 653-658
   Abstract »    Full Text »    PDF »
Introduction to the Series on MicroRNAs in the Cardiovascular System.
E. van Rooij (2012)
Circ. Res. 110, 481-482
   Abstract »    Full Text »    PDF »
Developing MicroRNA Therapeutics.
E. van Rooij, A. L. Purcell, and A. A. Levin (2012)
Circ. Res. 110, 496-507
   Abstract »    Full Text »    PDF »
MicroRNAs in Vascular and Metabolic Disease.
A. Zampetaki and M. Mayr (2012)
Circ. Res. 110, 508-522
   Abstract »    Full Text »    PDF »
MicroRNA therapeutics in cardiovascular medicine.
T. Thum (2012)
EMBO Mol Med. 4, 3-14
   Abstract »    Full Text »    PDF »
Early steps in steroidogenesis: intracellular cholesterol trafficking: Thematic Review Series: Genetics of Human Lipid Diseases.
W. L. Miller and H. S. Bose (2011)
J. Lipid Res. 52, 2111-2135
   Abstract »    Full Text »    PDF »
Translational control mechanisms in metabolic regulation: critical role of RNA binding proteins, microRNAs, and cytoplasmic RNA granules.
K. Adeli (2011)
Am J Physiol Endocrinol Metab 301, E1051-E1064
   Abstract »    Full Text »    PDF »
Maternal-foetal epigenetic interactions in the beginning of cardiovascular damage.
C. Napoli, T. Infante, and A. Casamassimi (2011)
Cardiovasc Res 92, 367-374
   Abstract »    Full Text »    PDF »
MicroRNA Modulation of Cholesterol Homeostasis.
C. Fernandez-Hernando, K. J. Moore, and W. C. Sessa (2011)
Arterioscler Thromb Vasc Biol 31, 2378-2382
   Abstract »    Full Text »    PDF »
MicroRNA-758 Regulates Cholesterol Efflux Through Posttranscriptional Repression of ATP-Binding Cassette Transporter A1.
C. M. Ramirez, A. Davalos, L. Goedeke, A. G. Salerno, N. Warrier, D. Cirera-Salinas, Y. Suarez, and C. Fernandez-Hernando (2011)
Arterioscler Thromb Vasc Biol 31, 2707-2714
   Abstract »    Full Text »    PDF »
MicroRNA-16 and MicroRNA-424 Regulate Cell-Autonomous Angiogenic Functions in Endothelial Cells via Targeting Vascular Endothelial Growth Factor Receptor-2 and Fibroblast Growth Factor Receptor-1.
A. Chamorro-Jorganes, E. Araldi, L. O. F. Penalva, D. Sandhu, C. Fernandez-Hernando, and Y. Suarez (2011)
Arterioscler Thromb Vasc Biol 31, 2595-2606
   Abstract »    Full Text »    PDF »
MicroRNAs regulating oxidative stress and inflammation in relation to obesity and atherosclerosis.
M. Hulsmans, D. De Keyzer, and P. Holvoet (2011)
FASEB J 25, 2515-2527
   Abstract »    Full Text »    PDF »
MicroRNA Replacement Therapy for miR-145 and miR-33a Is Efficacious in a Model of Colon Carcinoma.
A. F. Ibrahim, U. Weirauch, M. Thomas, A. Grunweller, R. K. Hartmann, and A. Aigner (2011)
Cancer Res. 71, 5214-5224
   Abstract »    Full Text »    PDF »
miR-33a/b contribute to the regulation of fatty acid metabolism and insulin signaling.
A. Davalos, L. Goedeke, P. Smibert, C. M. Ramirez, N. P. Warrier, U. Andreo, D. Cirera-Salinas, K. Rayner, U. Suresh, J. C. Pastor-Pareja, et al. (2011)
PNAS 108, 9232-9237
   Abstract »    Full Text »    PDF »
MicroRNA in ischemic stroke etiology and pathology.
C. Rink and S. Khanna (2011)
Physiol Genomics 43, 521-528
   Abstract »    Full Text »    PDF »
Cholesterol regulation of receptor-interacting protein 140 via microRNA-33 in inflammatory cytokine production.
P.-C. Ho, K.-C. Chang, Y.-S. Chuang, and L.-N. Wei (2011)
FASEB J 25, 1758-1766
   Abstract »    Full Text »    PDF »
A CHOP-regulated microRNA controls rhodopsin expression.
S. Behrman, D. Acosta-Alvear, and P. Walter (2011)
J. Cell Biol. 192, 919-927
   Abstract »    Full Text »    PDF »
Mouse models and the interpretation of human GWAS in type 2 diabetes and obesity.
R. D. Cox and C. D. Church (2011)
Dis. Model. Mech. 4, 155-164
   Abstract »    Full Text »    PDF »
Top Advances in Functional Genomics and Translational Biology for 2010.
A. D. Johnson and S. Prakash (2011)
Circ Cardiovasc Genet 4, 94-97
   Full Text »    PDF »
MicroRNAs in Metabolism and Metabolic Diseases.
V. Rottiers, S. H. Najafi-Shoushtari, F. Kristo, S. Gurumurthy, L. Zhong, Y. Li, D. E. Cohen, R. E. Gerszten, N. Bardeesy, R. Mostoslavsky, et al. (2011)
Cold Spring Harb Symp Quant Biol 76, 225-233
   Abstract »    Full Text »    PDF »
Intracellular Delivery Strategies for MicroRNAs and Potential Therapies for Human Cardiovascular Diseases.
M. A. Shi and G.-P. Shi (2010)
Science Signaling 3, pe40
   Abstract »    Full Text »    PDF »
Expression of miR-33 from an SREBP2 Intron Inhibits Cholesterol Export and Fatty Acid Oxidation.
I. Gerin, L.-A. Clerbaux, O. Haumont, N. Lanthier, A. K. Das, C. F. Burant, I. A. Leclercq, O. A. MacDougald, and G. T. Bommer (2010)
J. Biol. Chem. 285, 33652-33661
   Abstract »    Full Text »    PDF »
MicroRNA-33 encoded by an intron of sterol regulatory element-binding protein 2 (Srebp2) regulates HDL in vivo.
T. Horie, K. Ono, M. Horiguchi, H. Nishi, T. Nakamura, K. Nagao, M. Kinoshita, Y. Kuwabara, H. Marusawa, Y. Iwanaga, et al. (2010)
PNAS 107, 17321-17326
   Abstract »    Full Text »    PDF »
Reduced VLDL clearance in Apoe-/-Npc1-/- mice is associated with increased Pcsk9 and Idol expression and decreased hepatic LDL-receptor levels.
M. Ishibashi, D. Masson, M. Westerterp, N. Wang, S. Sayers, R. Li, C. L. Welch, and A. R. Tall (2010)
J. Lipid Res. 51, 2655-2663
   Abstract »    Full Text »    PDF »
HDL miR-ed Down by SREBP Introns.
M. S. Brown, J. Ye, and J. L. Goldstein (2010)
Science 328, 1495-1496
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882