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Anders Michael Naar, Ph.D.

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Our research is focused on elucidating molecular mechanisms of gene regulation, with emphasis on disease-associated pathways contributing to cholesterol/lipid disorders, certain types of cancers, and multidrug resistance in fungal infections.

Cholesterol/lipid regulation by the SREBP transcription factors

Part of our effort is centered on understanding how transcriptional regulators activate or repress target gene expression. One area of interest concerns the regulatory circuits governing cholesterol/lipid homeostasis. Aberrant regulation of cholesterol and other lipids contributes to major human diseases such as atherosclerosis, type 2 diabetes, metabolic syndrome, Alzheimer’s disease, and many types of cancers, thus highlighting the importance of understanding how cholesterol/lipid homeostasis is controlled. Our work on the sterol regulatory element-binding protein (SREBP) transcription factor family, master regulators of cholesterol/lipid biosynthesis and metabolism, has provided key mechanistic insights into gene regulatory pathways guiding metabolic homeostasis. For example, we have found that a speci?c subunit (ARC105/MED15) of the Mediator co-activator, a large multiprotein assembly, plays a critical role in mediating SREBP-dependent activation of genes controlling cholesterol/ lipid homeostasis (Yang et al. Nature 2006). Our studies have also revealed a critical role for orthologs of the NAD+-dependent deacetylase SIRT1 in negative regulation of SREBPs during fasting from C. elegans to mammals, with important implications for human cholesterol/lipid disorders (Walker et al. Genes Dev 2010). We have also uncovered a novel SREBP-regulatory feedback circuit linking production of the key membrane phospholipid phosphatidylcholine to SREBP-dependent control of hepatic lipogenesis (Walker et al. Cell 2011). These insights together may yield novel treatments for cardiometabolic diseases and cancers.

MicroRNA regulation of cholesterol/lipid homeostasis

Cholesterol and lipids are trafficked in the blood as lipoprotein particles, such as low-density lipoprotein (LDL) and high-density lipoprotein (HDL), which ferry their fatty cargo to different cells and tissues. Intriguingly, we have found conserved microRNAs (miR-33a/b) embedded within intronic sequences in the human SREBP genes. Our studies revealed that miR-33a/b target the cholesterol efflux pump ABCA1 for translational repression. ABCA1 is important for HDL synthesis and reverse cholesterol transport (RCT) from peripheral tissues, including macrophages/foam cells, and mutations in the ABCA1 gene have been implicated in atherosclerosis. These ?ndings suggest that miR-33a/b may represent novel targets of antisense-based therapeutics to ameliorate cardiovascular disease (Naja?-Shoushtari et al. Science 2010; Rottiers et al. CSH Symp Quant Biol 2012; Rottiers & Näär, Nature Rev. Mol. Cell Biol. 2012; Rottiers et al. Science Transl Med 2013).

We have pioneered a systematic and multi-pronged approach to comprehensively determine the roles of microRNAs and other noncoding RNAs in metabolic control and contribution to cardiometabolic diseases. Our analysis of GWAS in >188,000 people uncovered several microRNAs associated with cardiometabolic abnormalities. We have demonstrated that two of these microRNAs, miR-128-1 and miR-148a, control HDL-cholesterol and low-density lipoprotein-cholesterol (LDL-C) through direct regulation of ABCA1 and LDL receptor (LDLR) expression, respectively. Moreover, our in vivo studies show that LNA antimiRs directed against these microRNAs led to upregulation of the LDLR and ABCA1 in liver, with a concomitant bene?cial decrease in circulating LDL-C and increased HDL-C. Results from these studies indicate that microRNAs may indeed represent novel therapeutic targets for the treatment of cardiovascular disease (Wagschal et al., Nature Medicine 2015; Goedeke et al. Nature Medicine 2015).

Multidrug resistance in pathogenic fungi

Immunocompromised individuals, such as cancer patients undergoing chemotherapy are highly susceptible to fungal infections (e.g., Candida species), which frequently become drug-resistant upon antifungal treatment. We have elucidated the molecular mechanism by which the important human pathogenic fungus Candida glabrata becomes resistant to standard azole antifungal treatment (Thakur et al. Nature 2008). Our work has led to the identi?cation of a potent inhibitor of multidrug resistance (MDR) in C. glabrata. This compound exhibits efficacy in mouse models as a novel anti-MDR co-therapeutic to re- sensitize drug-resistant C. glabrata to standard azole treatment (Nishikawa et al. Nature 2016).

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Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
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  1. Näär AM. miR-33: A Metabolic Conundrum. Trends Endocrinol Metab. 2018 Apr 21. PMID: 29692333.
    View in: PubMed
  2. Lai L, Azzam KM, Lin WC, Rai P, Lowe JM, Gabor KA, Madenspacher JH, Aloor JJ, Parks JS, Näär AM, Fessler MB. MicroRNA-33 Regulates the Innate Immune Response via ATP Binding Cassette Transporter-mediated Remodeling of Membrane Microdomains. J Biol Chem. 2016 09 09; 291(37):19651-60. PMID: 27471270; PMCID: PMC5016698 [Available on 09/09/17].
  3. Goedeke L, Wagschal A, Fernández-Hernando C, Näär AM. miRNA regulation of LDL-cholesterol metabolism. Biochim Biophys Acta. 2016 12; 1861(12 Pt B):2047-2052. PMID: 26968099.
    View in: PubMed
  4. Nishikawa JL, Boeszoermenyi A, Vale-Silva LA, Torelli R, Posteraro B, Sohn YJ, Ji F, Gelev V, Sanglard D, Sanguinetti M, Sadreyev RI, Mukherjee G, Bhyravabhotla J, Buhrlage SJ, Gray NS, Wagner G, Näär AM, Arthanari H. Inhibiting fungal multidrug resistance by disrupting an activator-Mediator interaction. Nature. 2016 Feb 25; 530(7591):485-9. PMID: 26886795; PMCID: PMC4860947.
  5. Wagschal A, Najafi-Shoushtari SH, Wang L, Goedeke L, Sinha S, deLemos AS, Black JC, Ramírez CM, Li Y, Tewhey R, Hatoum I, Shah N, Lu Y, Kristo F, Psychogios N, Vrbanac V, Lu YC, Hla T, de Cabo R, Tsang JS, Schadt E, Sabeti PC, Kathiresan S, Cohen DE, Whetstine J, Chung RT, Fernández-Hernando C, Kaplan LM, Bernards A, Gerszten RE, Näär AM. Genome-wide identification of microRNAs regulating cholesterol and triglyceride homeostasis. Nat Med. 2015 Nov; 21(11):1290-7. PMID: 26501192; PMCID: PMC4993048.
  6. Goedeke L, Rotllan N, Canfrán-Duque A, Aranda JF, Ramírez CM, Araldi E, Lin CS, Anderson NN, Wagschal A, de Cabo R, Horton JD, Lasunción MA, Näär AM, Suárez Y, Fernández-Hernando C. MicroRNA-148a regulates LDL receptor and ABCA1 expression to control circulating lipoprotein levels. Nat Med. 2015 Nov; 21(11):1280-9. PMID: 26437365; PMCID: PMC4711995.
  7. Sedic M, Skibinski A, Brown N, Gallardo M, Mulligan P, Martinez P, Keller PJ, Glover E, Richardson AL, Cowan J, Toland AE, Ravichandran K, Riethman H, Naber SP, Näär AM, Blasco MA, Hinds PW, Kuperwasser C. Haploinsufficiency for BRCA1 leads to cell-type-specific genomic instability and premature senescence. Nat Commun. 2015 Jun 24; 6:7505. PMID: 26106036; PMCID: PMC4491827.
  8. Voth WP, Takahata S, Nishikawa JL, Metcalfe BM, Näär AM, Stillman DJ. A role for FACT in repopulation of nucleosomes at inducible genes. PLoS One. 2014; 9(1):e84092. PMID: 24392107; PMCID: PMC3879260.
  9. Rottiers V, Obad S, Petri A, McGarrah R, Lindholm MW, Black JC, Sinha S, Goody RJ, Lawrence MS, deLemos AS, Hansen HF, Whittaker S, Henry S, Brookes R, Najafi-Shoushtari SH, Chung RT, Whetstine JR, Gerszten RE, Kauppinen S, Näär AM. Pharmacological inhibition of a microRNA family in nonhuman primates by a seed-targeting 8-mer antimiR. Sci Transl Med. 2013 Nov 20; 5(212):212ra162. PMID: 24259050; PMCID: PMC4033576.
  10. Toiber D, Erdel F, Bouazoune K, Silberman DM, Zhong L, Mulligan P, Sebastian C, Cosentino C, Martinez-Pastor B, Giacosa S, D'Urso A, Näär AM, Kingston R, Rippe K, Mostoslavsky R. SIRT6 recruits SNF2H to DNA break sites, preventing genomic instability through chromatin remodeling. Mol Cell. 2013 Aug 22; 51(4):454-68. PMID: 23911928; PMCID: PMC3761390.
  11. Näär AM. Anti-atherosclerosis or No Anti-atherosclerosis: That is the miR-33 question. Arterioscler Thromb Vasc Biol. 2013 Mar; 33(3):447-8. PMID: 23407174; PMCID: PMC3880779.
  12. Rottiers V, Näär AM. MicroRNAs in metabolism and metabolic disorders. Nat Rev Mol Cell Biol. 2012 Mar 22; 13(4):239-50. PMID: 22436747; PMCID: PMC4021399.
  13. Rottiers V, Najafi-Shoushtari SH, Kristo F, Gurumurthy S, Zhong L, Li Y, Cohen DE, Gerszten RE, Bardeesy N, Mostoslavsky R, Näär AM. MicroRNAs in metabolism and metabolic diseases. Cold Spring Harb Symp Quant Biol. 2011; 76:225-33. PMID: 22156303; PMCID: PMC3880782.
  14. Walker AK, Jacobs RL, Watts JL, Rottiers V, Jiang K, Finnegan DM, Shioda T, Hansen M, Yang F, Niebergall LJ, Vance DE, Tzoneva M, Hart AC, Näär AM. A conserved SREBP-1/phosphatidylcholine feedback circuit regulates lipogenesis in metazoans. Cell. 2011 Nov 11; 147(4):840-52. PMID: 22035958; PMCID: PMC3384509.
  15. Näär AM. MiRs with a sweet tooth. Cell Metab. 2011 Aug 03; 14(2):149-50. PMID: 21803284; PMCID: PMC3880780.
  16. Mulligan P, Yang F, Di Stefano L, Ji JY, Ouyang J, Nishikawa JL, Toiber D, Kulkarni M, Wang Q, Najafi-Shoushtari SH, Mostoslavsky R, Gygi SP, Gill G, Dyson NJ, Näär AM. A SIRT1-LSD1 corepressor complex regulates Notch target gene expression and development. Mol Cell. 2011 Jun 10; 42(5):689-99. PMID: 21596603; PMCID: PMC3119599.
  17. Milbradt AG, Kulkarni M, Yi T, Takeuchi K, Sun ZY, Luna RE, Selenko P, Näär AM, Wagner G. Structure of the VP16 transactivator target in the Mediator. Nat Struct Mol Biol. 2011 Apr; 18(4):410-5. PMID: 21378963; PMCID: PMC3076674.
  18. Di Stefano L, Walker JA, Burgio G, Corona DF, Mulligan P, Näär AM, Dyson NJ. Functional antagonism between histone H3K4 demethylases in vivo. Genes Dev. 2011 Jan 01; 25(1):17-28. PMID: 21205864; PMCID: PMC3012933.
  19. Walker AK, Yang F, Jiang K, Ji JY, Watts JL, Purushotham A, Boss O, Hirsch ML, Ribich S, Smith JJ, Israelian K, Westphal CH, Rodgers JT, Shioda T, Elson SL, Mulligan P, Najafi-Shoushtari H, Black JC, Thakur JK, Kadyk LC, Whetstine JR, Mostoslavsky R, Puigserver P, Li X, Dyson NJ, Hart AC, Näär AM. Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP. Genes Dev. 2010 Jul 01; 24(13):1403-17. PMID: 20595232; PMCID: PMC2895199.
  20. Shahi P, Gulshan K, Näär AM, Moye-Rowley WS. Differential roles of transcriptional mediator subunits in regulation of multidrug resistance gene expression in Saccharomyces cerevisiae. Mol Biol Cell. 2010 Jul 15; 21(14):2469-82. PMID: 20505076.
    View in: PubMed
  21. Najafi-Shoushtari SH, Kristo F, Li Y, Shioda T, Cohen DE, Gerszten RE, Näär AM. MicroRNA-33 and the SREBP host genes cooperate to control cholesterol homeostasis. Science. 2010 Jun 18; 328(5985):1566-9. PMID: 20466882; PMCID: PMC3840500.
  22. Näär AM, Thakur JK. Nuclear receptor-like transcription factors in fungi. Genes Dev. 2009 Feb 15; 23(4):419-32. PMID: 19240130.
    View in: PubMed
  23. Thakur JK, Arthanari H, Yang F, Chau KH, Wagner G, Näär AM. Mediator subunit Gal11p/MED15 is required for fatty acid-dependent gene activation by yeast transcription factor Oaf1p. J Biol Chem. 2009 Feb 13; 284(7):4422-8. PMID: 19056732; PMCID: PMC3837390.
  24. Morris EJ, Ji JY, Yang F, Di Stefano L, Herr A, Moon NS, Kwon EJ, Haigis KM, Näär AM, Dyson NJ. E2F1 represses beta-catenin transcription and is antagonized by both pRB and CDK8. Nature. 2008 Sep 25; 455(7212):552-6. PMID: 18794899; PMCID: PMC3148807.
  25. Thakur JK, Arthanari H, Yang F, Pan SJ, Fan X, Breger J, Frueh DP, Gulshan K, Li DK, Mylonakis E, Struhl K, Moye-Rowley WS, Cormack BP, Wagner G, Näär AM. A nuclear receptor-like pathway regulating multidrug resistance in fungi. Nature. 2008 Apr 03; 452(7187):604-9. PMID: 18385733.
    View in: PubMed
  26. Beyer KS, Beauchamp RL, Lee MF, Gusella JF, Näär AM, Ramesh V. Mediator subunit MED28 (Magicin) is a repressor of smooth muscle cell differentiation. J Biol Chem. 2007 Nov 02; 282(44):32152-7. PMID: 17848560.
    View in: PubMed
  27. Binné UK, Classon MK, Dick FA, Wei W, Rape M, Kaelin WG, Näär AM, Dyson NJ. Retinoblastoma protein and anaphase-promoting complex physically interact and functionally cooperate during cell-cycle exit. Nat Cell Biol. 2007 Feb; 9(2):225-32. PMID: 17187060.
    View in: PubMed
  28. Yang F, Vought BW, Satterlee JS, Walker AK, Jim Sun ZY, Watts JL, DeBeaumont R, Saito RM, Hyberts SG, Yang S, Macol C, Iyer L, Tjian R, van den Heuvel S, Hart AC, Wagner G, Näär AM. An ARC/Mediator subunit required for SREBP control of cholesterol and lipid homeostasis. Nature. 2006 Aug 10; 442(7103):700-4. PMID: 16799563.
    View in: PubMed
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